Compounds as nuclear transport modulators and uses thereof

ABSTRACT

Nuclear transport modulators are disclosed. The compounds can inhibit nuclear transporters such as the exportin-1 transporter. The compounds and pharmaceutical compositions comprising the compounds can be used to treat neurological diseases and cancer.

This application is a continuation of U.S. application Ser. No.17/112,922, filed on Dec. 4, 2020, now allowed, which is a continuationof PCT International Application No. PCT/CN2019/090189, filed on Jun. 5,2019, which claims priority to PCT International Application No.PCT/CN2018/090151, filed on Jun. 6, 2018, each of which is incorporatedby reference in its entirety.

FIELD

The present invention relates to the field of medicinal technology, inparticular, to certain compounds, their preparation and uses, as well aspharmaceutical compositions comprising such compounds. As exemplified,the present invention relates to certain compounds as nuclear transportmodulators, their preparation, and the corresponding pharmaceuticalcompositions. The compounds and/or pharmaceutical compositions of thepresent invention can be potentially used in the manufacture of amedicament for preventing, treating, or ameliorating certain disorder ora disease in a patient, which includes, inter alio, a neurologicaldisorder or cancer. It is believed that the compounds and/orpharmaceutical compositions of the present invention exert theirtherapeutic benefits by, among other things, acting to modulateexportin-1 (XPO1) activities.

BACKGROUND

Since its initial functionality was published 10 years ago, exportin-1(as known as CRM-1 and XPO-1, has emerged as a key ‘carrier’ protein fortransporting some crucial growth regulatory proteins and tumorsuppressors from the nucleus to the cytoplasm of eukaryotic cells. Whenexportin-1's efflux becomes abnormally high (e.g., due to over-expressedXPO-1 production), depletion of these nuclear regulators can trigger awide variety of diseases (e.g., for some extensive listings: WO2017/117529 A1 and WO 2017/117535 A1).

For example, XPO1 is the sole nuclear exporter transporting the tumorsuppressors, e.g., p53, p27, FOXO1, IkB and it is overexpressed invarious sold tumors and hematological malignancies, such as GBM,ovarian, pancreatic, and cervical cancers, AML, MM, CLL, and NHL. Here,the main key point of XPO1 for cancer is overexpression of XPO1 proteinin multiple types of cancer cells, and its association with proliferatedcell cycle, depleting tumor suppressor proteins (e.g., p53, p27, FOXO1,IkB) in the nucleus, which allows cancer cells to grow (e.g., M. L.Crochiere, et. al., Oncotarget v.7, pp. 1863-1877 (2015). Selectiveinhibitors of nuclear exportin-1 (e.g., KPT-330,(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(pyrazin-2-yl)acrylohydrazide,a Karyopharm's SINE drug candidate) have begun clinical trials and haveshown promising clinical Phase 2 efficacy to treat some of thesecancers.

In general, Selective Inhibitor of Nuclear Export (SINE) compounds are afamily of small-molecules that inhibit nuclear export of cargo proteinsthrough covalent binding to cysteine 528 (Cys528) in the cargo-bindingpocket of Exportin 1 (XPO1, also called CRM1, chromosome maintenanceprotein 1) and exert anti-proliferative effects. The interaction betweenXPO1 and the activated small G-protein Ran (Ran-GTP) in the nucleusfacilitates the binding to cargo proteins containing a short amino acidsequence of hydrophobic residues called a nuclear export signal (NES).

Based on pre-clinical results, a similar pathology is also implicated inmany inflammatory, neurodegenerative and autoimmune diseases. As aconsequence, for example, glucocorticoids are widely usedanti-inflammatory and immunomodulatory drugs whose mechanism ofefficacy/action is mainly based on restoring enough steroid activatedglucocorticoid receptor (GR) to interfere against the excessiveactivities of transcription factors such as NF-κB in the nucleus. Asrevealed by its positive efficacy in animal models, KPT-350((Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-pivaloylacrylohydrazide)may have the potential to treat amyotrophic lateral sclerosis, multiplesclerosis, traumatic brain injury, epilepsy, systemic lupuserythematosus and rheumatoid arthritis.

While drugs inhibiting diseases caused by excessive XPO-1 efflux remainto be proven as clinically efficacious by the US FDA today, manydiseases still urgently need novel drug treatments. For an example, USFDA has not yet approved sales of any drug to specifically treattraumatic brain injury (e.g., concussions) which annually afflicts atleast 1.7 million Americans. As a second urgent need, ˜30% of epilepticpatients are/become unfortunately resistant to FDA currently approveddrugs. As a third example, patients afflicted with rare glioblastoma (upto ˜3.7 per 100,000 age adjusted incidence rate in surveyed Europeancountries have very poor prognosis (e.g., relative 5-year survival ratesreach up to 4.4% by the same survey).

SUMMARY

The following is only an overview of some aspects of the presentinvention but is not limited thereto. All references of thisspecification are incorporated herein by reference in their entirety.When the disclosure of this specification is different with citations,the disclosure of this specification shall prevail. The presentinvention provides compounds and pharmaceutical compositions whichmodulate exportin-1 activities, their preparation, and the correspondingpharmaceutical compositions. The compounds and/or pharmaceuticalcompositions of the present invention can be potentially used in themanufacture of a medicament for preventing, treating, amelioratingcertain disorder or a disease in a patient associated with exportin-1activities, which includes, inter alia, certain neurological disordersor cancer.

One aspect of the present invention is the provision of a compoundhaving the structure of Formula (I′), Formula (II′) or Formula (III′):

-   -   a stereoisomer, an N-oxide, a solvate, a metabolite, a        pharmaceutically acceptable salt or a prodrug thereof, wherein,        -   R¹ is independently selected from —C(═O)—R², C₃₋₆            heterocycloalkyl, C₅₋₁₀ heteroaryl; any heterocycloalkyl or            heteroaryl of R¹ is optionally independently substituted            with one, or more substituents selected from the group            consisting of deuterium, —OH, —SH, —NO₂, halogen, amino,            cyano, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂            alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy and C₁₋₁₂            alkylsulfanyl; and        -   R² is independently selected from C₁₋₆ alkyl, C₃₋₆            cycloalkyl, C₃₋₆ heterocycloalkyl; any alkyl, cycloalkyl,            heterocycloalkyl of R² is optionally and independently            substituted with one or more substituents selected from the            group consisting of halogen, amino, cyano, C₁₋₁₂ alkyl,            C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl,            C₁₋₁₂ haloalkoxy and C₁₋₁₂ alkylsulfanyl; and        -   R³, R⁴ are independently selected from C₁₋₆ alkyl,            substituted C₁₋₆ alkyl, or R³ and R⁴ together with N which            they are attached form a substituted or unsubstituted C₄₋₁₀            cycloalkylamino; any alkyl or cycloalkylamino of R³ and R⁴            is optionally and independently substituted with one or more            substituents selected from the group consisting of halogen,            amino, cyano, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,            C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy and C₁₋₁₂            alkylsulfanyl.

In a further aspect, the invention relates to pharmaceuticalcompositions each comprising an effective amount of at least onecompound of Formula (I′-III′) or a pharmaceutically acceptable salt of acompound of Formula (I′-III′). Pharmaceutical compositions according tothe invention may further comprise at least one pharmaceuticallyacceptable excipient, carrier, adjuvant, solvent, support or acombination thereof.

In another aspect, the invention is directed to a method of treating asubject suffering from a disorder or a disease, which includes, interalia, certain neurological disorders or cancer, by modulating exportin-1activities, comprising administering to the subject in need of suchtreatment an effective amount of at least one compound of Formula(I′-III′) or a pharmaceutically acceptable salt of a compound of Formula(I′-III′), or comprising administering to the subject in need of suchtreatment an effective amount of a pharmaceutical composition comprisingan effective amount of at least one compound of Formula (I′-III′) or apharmaceutically acceptable salt of a compound of Formula (I′-III′).

In yet another aspect, the invention is directed to a method of treatinga subject suffering from certain neurological disorders or diseases,which disorders or diseases comprise amyotrophic lateral sclerosis,epilepsy, traumatic brain injuries, Huntington's disease, Parkinson'sdisease, rheumatoid arthritis, systemic lupus erythematosus.

In still another aspect, the invention is directed to a method oftreating a subject suffering from a cancer, which comprises lymphoma,liposarcoma, multiple myeloma, myelodysplastic syndrome, prostatecancer, colorectal cancer, endometrial cancer, pancreatic cancer,gastric cancer, diffuse large B-cell lymphoma, non-small cell lungcancer, ovarian carcinoma, breast cancer, acute myeloid leukemia,thymoma, esophageal cancer, glioblastoma, and other solid tumors.

An aspect of the present invention concerns the use of compound ofFormula (I′-III′) for the preparation of a medicament used in thetreatment, prevention, inhibition or elimination of certain neurologicaldisorders or cancer, which medicament further comprises adjunctivetherapies, such as radiation, or therapeutically effective amounts ofone or more, optional, adjunctive active ingredients, which adjunctiveactive ingredients comprise a chemotherapeutic agent, a TK or RTKinhibitor, a BCL2 inhibitor, a FLT3 inhibitor, a EGFR inhibitor, apro-apoptotic drug, an antibody-drug conjugate (ADC), an immunecheckpoint inhibitor, CAR-T, a personalized cancer vaccine, and achemokine/cytokine.

In yet another aspect of the present invention, the compounds of Formula(I′-III′) and pharmaceutically acceptable salts thereof are useful asmodulators of XPO1 activities. Thus, the invention is directed to amethod for modulating XPO1 activities in a subject, comprising exposingthe subject to an effective amount of at least one compound of Formula(I′-III′) or a pharmaceutically acceptable salt of a compound of Formula(I′-III′).

In yet another aspect, the present invention is directed to methods ofmaking compounds of Formula (I′-III′) and pharmaceutically acceptablesalts thereof.

In certain embodiments of the compounds, pharmaceutical compositions,and methods of the invention, the compound of Formula (I′-III′) is acompound selected from those species described or exemplified in thedetailed description below or is a pharmaceutically acceptable salt ofsuch a compound.

Another preferred embodiment, the present invention is directed tomethods of preparing pharmaceutical compositions each comprising aneffective amount of at least one compound of Formula (I′-III′) or apharmaceutically acceptable salt of a compound of Formula (I′-III′).Pharmaceutical compositions according to the invention may furthercomprise at least one pharmaceutically acceptable excipient, carrier,adjuvant, solvent, support or a combination thereof.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described herein (oras known to those skilled in the art) and the other pharmaceuticallyactive agents or treatments within its dosage range. For example, theCDC2 inhibitor olomucine has been found to act synergistically withknown cytotoxic agents in inducing apoptosis (J. Cell Sci., (1995) 108,2897). The compounds of the invention may also be administeredsequentially with known anticancer or cytotoxic agents when acombination formulation is inappropriate. In any combination treatment,the invention is not limited in the sequence of administration;compounds of Formula (I′-III′) may be administered either prior to orafter administration of the known anticancer or cytotoxic agent. Forexample, the cytotoxic activity of the cyclin-dependent kinase inhibitorflavopiridol is affected by the sequence of administration withanticancer agents (Cancer Research, (1997) 57, 3375). Such techniquesare within the skills of persons skilled in the art as well as attendingphysicians.

Any of the aforementioned methods may be augmented by administration offluids (such as water), loop diuretics, one or more of achemotherapeutic or antineoplastic agent, such as leucovorin andfluorouracil, and an adjunctive chemotherapeutic agent (such asfilgrastim and erythropoietin), or any combination of the foregoing.

Yet another embodiment is a method for administering a compound of theinstant invention to a subject (e.g., a human) in need thereof byadministering to the subject the pharmaceutical formulation of thepresent invention.

Yet another embodiment is a method of preparing a pharmaceuticalformulation of the present invention by mixing at least onepharmaceutically acceptable compound of the present invention, and,optionally, one or more pharmaceutically acceptable additives orexcipients.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, beads, cachets andsuppositories. The powders and tablets may be comprised of from about 5to about 95 percent active ingredient. Suitable solid carriers are knownin the art, e.g., magnesium carbonate, magnesium stearate, talc, sugaror lactose. Tablets, powders, cachets and capsules can be used as soliddosage forms suitable for oral administration. Examples ofpharmaceutically acceptable carriers and methods of manufacture forvarious compositions may be found in A. Gennaro (ed.), Remington'sPharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co.,Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example, may be mentioned water or water-propylene glycolsolutions for parenteral injection or addition of sweeteners andopacifiers for oral solutions, suspensions and emulsions. Liquid formpreparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g., nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compounds of this invention may also be delivered subcutaneously.

Preferably the compound is administered orally or intravenously.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 1000 mg, preferably fromabout 1 mg to about 500 mg, more preferably from about 1 mg to about 250mg, still more preferably from about 1 mg to about 200 mg, according tothe particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required. Theamount and frequency of administration of the compounds of the inventionand/or the pharmaceutically acceptable salts thereof will be regulatedaccording to the judgment of the attending clinician considering suchfactors as age, condition and size of the patient as well as severity ofthe symptoms being treated. A typical recommended daily dosage regimenfor oral administration can range from about 1 mg/day to about 200mg/day, in one to two divided doses.

Any embodiment disclosed herein can be combined with other embodimentsas long as they are not contradictory to one another, even though theembodiments are described under different aspects of the invention. Inaddition, any technical feature in one embodiment can be applied to thecorresponding technical feature in other embodiments as long as they arenot contradictory to one another, even though the embodiments aredescribed under different aspects of the invention.

The foregoing merely summarizes certain aspects disclosed herein and isnot intended to be limiting in nature. These aspects and other aspectsand additional embodiments, features, and advantages of the inventionwill be apparent from the following detailed description and throughpractice of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other aspects and advantages of embodiments of the presentdisclosure will become apparent and more readily appreciated from thefollowing descriptions made with reference the accompanying schemes anddrawings, in which:

FIGS. 1A-1C show the EC50 of XPO1 inhibition by Compound III in REV-GFPU2OS assay.

FIGS. 2A-2B show EC50 in REV cargo inhibition, and it did not affectcell viability.

FIGS. 3A-3C show sustained XPO1 inhibition by LMB in washout study.

FIGS. 4A-4C show Compound III exhibited XPO1 inhibition and theinhibition was abrogated 24 hours post washout in REV-GFP U2OS assay.

FIG. 5 shows the comparison of brain behavior of Compound III withKPT-350 in cassette PK of brain penetration.

FIG. 6 shows the percent of body weight change of mice receivingCompound III in MTD study.

FIG. 7 shows tumor growth inhibition by Compound III in glioblastomaU87-Luc orthotopic xenograft model.

FIG. 8 shows the survival curve of vehicle vs Compound III-treatedgroups of tumor-bearing mice following 4 weeks of Compound III (20mg/kg, tiw) treatment.

FIG. 9 shows body weight changes during and following treatment (Day7-Day 65).

FIGS. 10A-10B illustrate the decrease in Ki67 and CRM1 by XPO1 CompoundIII in PD study of U87-luc orthotopic xenograft model.

FIG. 11 shows the percent cell growth relative to control followingincubation with KPT-330 in a cell proliferation assay.

FIG. 12 shows the percent cell growth relative to control followingincubation with certain compounds provided by the present disclosure ina cell proliferation assay.

FIGS. 13A-13C show the EC50 of XPO1 inhibition by Compound I andCompound III in the REV-GFP U2OS assay.

FIGS. 14-16 show the inhibition of cell growth in T98G, LN-229, and U251cells, respectively, following incubation with various compounds.

DETAILED DESCRIPTION

For the sake of brevity, the disclosures of the publications cited inthis specification, including patents and patent applications, areherein incorporated by reference in their entirety.

Most chemical names were generated using IUPAC nomenclature herein. Somechemical names were generated using different nomenclatures oralternative or commercial names known in the art. In the case ofconflict between names and structures, the structures prevail.

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. The invention is intended to cover allalternatives, modifications and equivalents which may be included withinthe scope of the present invention as defined by the claims. One skilledin the art will recognize many methods and materials similar orequivalent to those described herein, which could be used in thepractice of the present invention. The present invention is in no waylimited to the methods and materials described herein. In the event thatone or more of the incorporated literatures, patents, and similarmaterials differs from or contradicts this application, including butnot limited to defined terms, term usage, described techniques, or thelike, this application controls.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable sub-combination.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as are commonly understood by one skilled in theart to which this invention belongs. All patents and publicationsreferred to herein are incorporated by reference in their entirety.

As used herein, the following definitions shall apply unless otherwiseindicated. For purposes of this invention, the chemical elements areidentified in accordance with the Periodic Table of the Elements, CASversion, and the Handbook of Chemistry and Physics, 75th Ed. 1994.Additionally, general principles of organic chemistry are described inOrganic Chemistry, Thomas Sorrell, University Science Books, Sausalito,1999, and March's Advanced Organic Chemistry by Michael B. Smith andJerry March, John Wiley & Sons, New York, 2007.

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings. If a definition is missing, the conventional definition asknown to one skilled in the art controls. If a definition providedherein conflicts or is different from a definition provided in any citedpublication, the definition provided herein controls.

As used herein, the terms “including”, “containing”, and “comprising”are used in their open, non-limiting sense.

As used herein, the singular forms “a”, “an”, and “the” include pluralreferents unless the context clearly dictates otherwise.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

As used herein, “alkyl” refers to a saturated, straight- orbranched-chain hydrocarbon group having from 1 to 12 carbon atoms.Representative alkyl groups include, but are not limited to, methyl,ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl,2-methyl-1-butyl, 3-methyl-1-butyl, methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl,neopentyl, n-hexyl, and the like, and longer alkyl groups, such asheptyl, octyl, and the like. As used herein, “lower alkyl” means analkyl having from 1 to 6 carbon atoms.

The term “alkylamino” as used herein denotes an amino group as definedherein wherein one hydrogen atom of the amino group is replaced by analkyl group as defined herein. Aminoalkyl groups can be defined by thefollowing general formula —NH-alkyl. This general formula includesgroups of the following general formula: —NH—C₁-C₁₀ alkyl and —NH—C₁-C₆alkyl. Examples of aminoalkyl groups include, but are not limited toaminomethyl, aminoethyl, aminopropyl, aminobutyl.

The term “dialkylamino” as used herein denotes an amino group as definedherein wherein two hydrogen atoms of the amino group are replaced byalkyl groups as defined herein. Diaminoalkyl groups can be defined bythe following general formula —N(alkyl)₂, wherein the alkyl groups canbe the same or can be different and can be selected from alkyls asdefined herein, for example C₁-C₁₀ alkyl or C₁-C₆ alkyl.

The term “alkoxy” as used herein includes —O-(alkyl), wherein alkyl isdefined above.

As used herein, “alkoxyalkyl” means -(alkylenyl)-O-(alkyl), wherein each“alkyl” is independently an alkyl group defined above.

The term “amino” as used herein refers to an —NH₂ group.

“Aryl” means a mono-, bi-, or tricyclic aromatic group, wherein allrings of the group are aromatic. For bi- or tricyclic systems, theindividual aromatic rings are fused to one another. Exemplary arylgroups include, but are not limited to, phenyl, naphthalene, andanthracene.

“Aryloxy” as used herein refers to an —O-(aryl) group, wherein aryl isdefined as above.

“Arylalkyl” as used herein refers to an -(alkylenyl)-(aryl) group,wherein alkylenyl and aryl are as defined above. Non-limiting examplesof arylalkyls comprise a lower alkyl group. Non-limiting examples ofsuitable arylalkyl groups include benzyl, 2-phenethyl, andnaphthalenylmethyl.

“Arylalkoxy” as used herein refers to an —O-(alkylenyl)-aryl groupwherein alkylenyl and aryl are as defined above.

The term “cyano” as used herein means a substituent having a carbon atomjoined to a nitrogen atom by a triple bond.

The term “cyanoalkyl” denotes an alkyl group as defined above wherein ahydrogen atom of the alkyl group is replaced by a cyano (—CN) group. Thealkyl portion of the cyanoalkyl group provides the connection point tothe remainder of the molecule.

The term “deuterium” as used herein means a stable isotope of hydrogenhaving one proton and one neutron.

The term “halogen” as used herein refers to fluorine, chlorine, bromine,or iodine. The term “halo” represents chloro, fluoro, bromo, or iodo.

The term “haloalkyl” denotes an alkyl group as defined above wherein oneor more, for example one, two, or three of the hydrogen atoms of thealkyl group are replaced by a halogen atom, for example fluoro, bromo,or chloro, in particular fluoro. Examples of haloalkyl include, but arenot limited to, monofluoro-, difluoro-, or trifluoro-methyl, -ethyl or-propyl, for example, 3,3,3-trifluoropropyl, 2-fluoroethyl,2,2,2-trifluoroethyl, fluoromethyl, difluoromethyl, or trifluoromethyl,or bromoethyl or chloroethyl. Similarly, the term “fluoroalkyl” refersto an alkyl group as defined above substituted with one or more, forexample one, two, or three fluorine atoms.

The term “haloalkoxy” as used herein refers to an —O-(haloalkyl) groupwherein haloalkyl is defined as above. Exemplary haloalkoxy groups arebromoethoxy, chloroethoxy, trifluoromethoxy and 2,2,2-trifluoroethoxy.

The term “hydroxy” means an —OH group.

The term “hydroxyalkyl” denotes an alkyl group that is substituted by atleast one hydroxy group, for example, one, two or three hydroxygroup(s). The alkyl portion of the hydroxyalkyl group provides theconnection point to the remainder of a molecule. Examples ofhydroxyalkyl groups include, but are not limited to, hydroxymethyl,hydroxyethyl, 1-hydroxypropyl, 2-hydroxyisopropyl, 1,4-dihydroxybutyl,and the like.

The term “oxo” means an ═O group and may be attached to a carbon atom ora sulfur atom. The term “N-oxide” refers to the oxidized form of anitrogen atom.

As used herein, the term “cycloalkyl” refers to a saturated or partiallysaturated, monocyclic, fused polycyclic, bridged polycyclic, or spiropolycyclic carbocycle having from 3 to 12 ring carbon atoms. Anon-limiting category of cycloalkyl groups are saturated or partiallysaturated, monocyclic carbocycles having from 3 to 6 carbon atoms.Illustrative examples of cycloalkyl groups include, but are not limitedto, the following moieties:

The term “cycloalkoxy” refers to a —O-(cycloalkyl) group.

As used herein, the term “heteroaryl” refers to a monocyclic, or fusedpolycyclic, aromatic heterocycle having from 3 to 15 ring atoms that areselected from carbon, oxygen, nitrogen, selenium and sulfur. Suitableheteroaryl groups do not include ring systems that must be charged to bearomatic, such as pyrylium. Some suitable 5-membered heteroaryl rings(as a monocyclic heteroaryl or as part of a polycyclic heteroaryl) haveone oxygen, sulfur, or nitrogen atom, or one nitrogen plus one oxygen orsulfur, or 2, 3, or 4 nitrogen atoms. Some suitable 6-memberedheteroaryl rings (as a monocyclic heteroaryl or as part of a polycyclicheteroaryl) have 1, 2, or 3 nitrogen atoms. Examples of heteroarylgroups include, but are not limited to, pyridinyl, imidazolyl,imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl,benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, and furopyridinyl.

The term “bicyclic heteroaryl” refers to a heteroaryl as defined above,having two constituent aromatic rings, wherein the two rings are fusedto one another and at least one of the rings is a heteroaryl as definedabove. Bicyclic heteroaryls include bicyclic heteroaryl groupscomprising 1, 2, 3, or 4 heteroatom ring members and are unsubstitutedor substituted with one or more substituents selected from the groupconsisting of amino and halo; and wherein one or more N ring members ofsaid heteroaryl is optionally an N-oxide.

Those skilled in the art will recognize that the species of heteroaryl,and cycloalkyl groups listed or illustrated above are not exhaustive,and that additional species within the scope of these defined terms mayalso be selected.

As described herein, compounds disclosed herein may optionally besubstituted with one or more substituents, or as exemplified byparticular classes, subclasses, and species of the invention.

As used herein, the term “substituted” means that the specified group ormoiety bears one or more suitable substituents. As used herein, the term“unsubstituted” means that the specified group bears no substituents. Asused herein, the term “optionally substituted” means that the specifiedgroup is unsubstituted or substituted by the specified number ofsubstituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system. “Substituted” refers to a groupin which one or more hydrogen atoms are independently replaced with thesame or different substituent(s). Each substituent can be independentlyselected from deuterio, halogen, —OH, —CN, —CF₃, —OCF₃, ═O, —NO₂, C₁₋₆alkoxy, C₁₋₆ alkyl, —COOR, —NR₂, and —CONR₂; wherein each R isindependently selected from hydrogen and C₁₋₆ alkyl. Each substituentcan be independently selected from deuterio, halogen, —NH₂, —OH, C₁₋₃alkoxy, and C₁₋₃ alkyl, trifluoromethoxy, and trifluoromethyl. Eachsubstituent can be independently selected from deuterio, —OH, methyl,ethyl, trifluoromethyl, methoxy, ethoxy, and trifluoromethoxy. Eachsubstituent can be selected from deuterio, C₁₋₃ alkyl, ═O, C₁₋₃ alkyl,C₁₋₃ alkoxy, and phenyl. Each substituent can be selected from deuterio,—OH, —NH₂, C₁₋₃ alkyl, and C₁₋₃ alkoxy.

As used herein, the expression “one or more substituents” denotes one tomaximum possible number of substitution(s) that can occur at anyvalency-allowed position on the system. In a certain embodiment, one ormore substituent means 1, 2, 3, 4, or 5 substituents. In anotherembodiment, one or more substituent means 1, 2, or 3 substituents.

As used herein, the double bond in Formula II′ bearing its substituentsattached with “

” bonds represents either an E or Z configuration.

Any atom that is represented herein with an unsatisfied valence isassumed to have the sufficient number of hydrogen atoms to satisfy theatom's valence.

When any variable (e.g., alkyl, alkylenyl, heteroaryl, R¹, R²) appearsin more than one place in any formula or description provided herein,the definition of that variable on each occurrence is independent of itsdefinition at every other occurrence.

Numerical ranges, as used herein, are intended to include sequentialwhole numbers. For example, a range expressed as “from 0 to 4” or “0-4”includes 0, 1, 2, 3 and 4, while a range expressed as “10-20%” includes10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% and 20%. Similarly,numerical ranges are also intended to include sequential fractionalintegers. For example, a range expressed as “1-2%” would include 1.0%,1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9% and 2.0%.

When a multifunctional moiety is shown, the point of attachment to thecore is indicated by a line or hyphen. For example, aryloxy—refers to amoiety in which an oxygen atom is the point of attachment to the coremolecule while aryl is attached to the oxygen atom.

As used herein, the term “subject” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans; non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;and laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In one embodiment of the presentinvention, the mammal is a human.

“Patient” includes both human and animals.

The term “inhibitor” refers to a molecule such as a compound, a drug, anenzyme activator, or a hormone that blocks or otherwise interferes witha particular biologic activity.

The term “modulator” refers to a molecule, such as a compound of thepresent invention, that increases or decreases, or otherwise affects theactivity of a given protein, receptor and/or ion channels.

The terms “effective amount” or “therapeutically effective amount” referto a sufficient amount of the agent to provide the desired biologicalresult. That result can be reduction and/or alleviation of the signs,symptoms, or causes of a disease or medical condition, or any otherdesired alteration of a biological system. For example, an “effectiveamount” for therapeutic use is the amount of a compound, or of acomposition comprising the compound, that is required to provide aclinically relevant change in a disease state, symptom, or medicalcondition. An appropriate “effective” amount in any individual case maybe determined by one of ordinary skill in the art using routineexperimentation. Thus, the expression “effective amount” generallyrefers to the quantity for which the active substance has atherapeutically desired effect.

As used herein, the terms “treat” or “treatment” encompass both“preventative” and “curative” treatment. “Preventative” treatment ismeant to indicate a postponement of development of a disease, a symptomof a disease, or medical condition, suppressing symptoms that mayappear, or reducing the risk of developing or recurrence of a disease orsymptom. “Curative” treatment includes reducing the severity of orsuppressing the worsening of an existing disease, symptom, or condition.Thus, treatment includes ameliorating or preventing the worsening ofexisting disease symptoms, preventing additional symptoms fromoccurring, ameliorating or preventing the underlying metabolic causes ofsymptoms, inhibiting the disorder or disease, e.g., arresting thedevelopment of the disorder or disease, relieving the disorder ordisease, causing regression of the disorder or disease, relieving acondition caused by the disease or disorder, or stopping the symptoms ofthe disease or disorder.

As used herein, the terms “administration of” and “administering a”compound should be understood to mean providing a compound of theinvention, pharmaceutical composition comprising a compound or a prodrugof a compound of the invention to an individual in need thereof. It isrecognized that one skilled in the non-limiting art can treat a patientpresently afflicted with neurological and psychiatric disorders or byprophylactically treat a patient afflicted with the disorders with aneffective amount of the compound of the present invention.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationsof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s) and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from a combination, complexation or aggregation of anytwo or more of the ingredients, or from the other types of reactions orinteractions such as to cause the dissociation of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by mixing a compound of thepresent invention and a pharmaceutically acceptable carrier.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. For example, compounds of any formula given hereinmay have asymmetric or chiral centers and therefore exist in differentstereoisomeric forms. All stereoisomers, including optical isomers,enantiomers, and diastereomers, of the compounds of the general formula,and mixtures thereof, are considered to fall within the scope of theformula. Furthermore, certain structures may exist as geometric isomers(i.e., cis and trans isomers), as tautomers, or as atropisomers. Allsuch isomeric forms, and mixtures thereof, are contemplated herein aspart of the present invention. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more tautomeric or atropisomericforms, and mixtures thereof.

“Stereoisomer” refers to compounds which have identical chemicalconstitution but differ with regard to the arrangement of the atoms orgroups in space. Stereoisomers include enantiomer, diastereomers,conformer (rotamer), geometric (cis/trans) isomer, atropisomer etc.

“Chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

“Enantiomers” refers to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g., melting points,boiling points, spectral properties or biological activities. A mixtureof diastereomers may be separated under high resolution analyticalprocedures such as electrophoresis and chromatography such as HPLC.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York,1994.

Many organic compounds exist in optically active forms, i.e., they havethe ability to rotate the plane of polarized light. In describing anoptically active compound, the prefixes D and L, or R and S, are used todenote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and/or (+) and (−) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)or l meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. A specific stereoisomer may be referred toas an enantiomer, and a mixture of such stereoisomers is called anenantiomeric mixture. A 50:50 mixture of enantiomers is referred to as aracemic mixture or a racemate, which may occur where there has been nostereoselection or stereospecificity in a chemical reaction or process.

Any asymmetric atom (e.g., carbon or the like) of the compound(s)disclosed herein can be in racemic or enantiomerically enriched, forexample the (R)-, (S)- or (R, S)-configuration. In certain embodiments,each asymmetric atom has at least 50% enantiomeric excess, at least 60%enantiomeric excess, at least 70% enantiomeric excess, at least 80%enantiomeric excess, at least 90% enantiomeric excess, at least 95%enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or(5)-configuration.

Depending on the choice of the starting materials and procedures, thecompounds can be present in the form of one of the possiblestereoisomers or as mixtures thereof, such as racemates anddiastereoisomer mixtures, depending on the number of asymmetric carbonatoms. Optically active (R)- and (S)-isomers may be prepared usingchiral synthons or chiral reagents or resolved using conventionaltechniques. If the compound contains a double bond, the substituent maybe E or Z configuration. If the compound contains a disubstitutedcycloalkyl, a cycloalkyl substituent may have a cis- ortrans-configuration relative to another substituent of the samecycloalkyl frame.

Any resulting mixtures of stereoisomers can be separated on the basis ofthe physicochemical differences of the constituents, into the pure orsubstantially pure geometric isomers, enantiomers, diastereomers, forexample, by chromatography and/or fractional crystallization. Anyresulting racemates of final products or intermediates can be resolvedinto the optical antipodes by methods known to those skilled in the art,e.g., by separation of the diastereomeric salts thereof. Racemicproducts can also be resolved by chiral chromatography, e.g., highperformance liquid chromatography (HPLC) using a chiral adsorbent.Preferred enantiomers can also be prepared by asymmetric syntheses. See,for example, Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis(2nd Ed. Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, U K, 2012);Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, N Y,1962); Wilen, S. H., Tables of Resolving Agents and Optical Resolutionsp. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN1972); Chiral Separation Techniques: A Practical Approach (Subramanian,G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

Diastereomeric mixtures may be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers may beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride, orformation of a mixture of diastereomeric salts), separating thediastereomers and converting (e.g., hydrolyzing or de-salting) theindividual diastereomers to the corresponding pure enantiomers.Enantiomers may also be separated by use of chiral HPLC column.

The compounds of the invention can form pharmaceutically acceptablesalts, which are also within the scope of this invention. A“pharmaceutically acceptable salt” refers to a salt of a free acid orbase of a compound of Formula (I′) that is non-toxic, is physiologicallytolerable, is compatible with the pharmaceutical composition in which itis formulated, and is otherwise suitable for formulation and/oradministration to a subject. Reference to a compound herein isunderstood to include reference to a pharmaceutically acceptable salt ofsaid compound unless otherwise indicated.

Compound salts include acidic salts formed with inorganic and/or organicacids, as well as basic salts formed with inorganic and/or organicbases. In addition, where a given compound contains both a basic moiety,such as, but not limited to, a pyridine or imidazole, and an acidicmoiety, such as, but not limited to, a carboxylic acid, one of skill inthe art will recognize that the compound may exist as a zwitterion(“inner salt”); such salts are included within the term “salt” as usedherein. Salts of the compounds of the invention may be prepared, forexample, by reacting a compound with an amount of a suitable acid orbase, such as an equivalent amount, in a medium such as one in which thesalt precipitates or in an aqueous medium followed by lyophilization.

Exemplary salts include, but are not limited, to sulfate, citrate,acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate,phosphate, acid phosphate, isonicotinate, lactate, salicylate, acidcitrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, fumarate, gluconate, glucuronate,saccharate, formate, benzoate, glutamate, methanesulfonate (“mesylate”),ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate(i.e., 1,1′-methylene-bis(2-hydroxy-3-naphthoate)) salts. Apharmaceutically acceptable salt may involve the inclusion of anothermolecule such as an acetate ion, a succinate ion or other counterion.The counterion may be any organic or inorganic moiety that stabilizesthe charge on the parent compound. Furthermore, a pharmaceuticallyacceptable salt may have more than one charged atom in its structure.Instances where multiple charged atoms are part of the pharmaceuticallyacceptable salt can have multiple counterions. Hence, a pharmaceuticallyacceptable salt can have one or more charged atoms and/or one or morecounter ion.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates) and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, tert-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g., decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others.

Additionally, acids and bases which are generally considered suitablefor the formation of pharmaceutically useful salts from pharmaceuticalcompounds are discussed, for example, by P. Stahl et al, Camille G.(eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use,(2002) Zurich: Wiley-VCH; S. Berge et al, Journal of PharmaceuticalSciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics(1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry(1996), Academic Press, New York; and in The Orange Book (Food & DrugAdministration, MD, available from FDA). These disclosures areincorporated herein by reference thereto.

Additionally, any compound described herein is intended to refer also toany unsolvated form, or a hydrate, solvate, or polymorph of such acompound, and mixtures thereof, even if such forms are not listedexplicitly. “Solvate” means a physical association of a compound of theinvention with one or more solvent molecules. This physical associationinvolves varying degrees of ionic and covalent bonding, includinghydrogen bonding. In certain instance the solvate will be capable ofisolation, for example when one or more solvent molecules areincorporated in the crystal lattice of a crystalline solid. “Solvate”encompasses both solution-phase and isolatable solvates. Suitablesolvates include those formed with pharmaceutically acceptable solventssuch as water, ethanol, and the like. In some embodiments, the solventis water and the solvates are hydrates.

One or more compounds of the invention may optionally be converted to asolvate. Methods for the preparation of solvates are generally known.Thus, for example, M. Caira et al., J. Pharmaceutical Sci., 93(3),601-611 (2004), describes the preparation of the solvates of theantifungal fluconazole in ethyl acetate as well as from water. Similarpreparations of solvates, hemisolvate, hydrates, and the like aredescribed by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). Atypical, non-limiting process involves dissolving the compound of theinvention in a suitable amount of the solvent (organic solvent or wateror a mixture thereof) at a higher than ambient temperature and coolingthe solution at a rate sufficient to form crystals which are thenisolated by standard methods. Analytical techniques such as, forexample, infrared spectroscopy, show the presence of the solvent (orwater) in the crystals as a solvate (or hydrate).

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶Cl, and ¹²⁵I. respectively. Such isotopically labelled compoundsare useful in metabolic studies (for example with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques[such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or ¹¹C labeled compound may be particularly suitablefor PET or SPECT studies. Further, substitution with heavier isotopessuch as deuterium (i.e., ²H) may afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements. Isotopically labeledcompounds of this invention can generally be prepared by carrying outthe procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

The use of the terms “salt,” “solvate,” “polymorph,” and the like, withrespect to the compounds described herein is intended to apply equallyto the salt, solvate, and polymorph forms of enantiomers, stereoisomers,rotamers, tautomers, atropisomers, and racemates of the compounds of theinvention.

The chemical nomenclature tool is the software of ChemDraw Professional16.0.

The present invention relates to particular molecules andpharmaceutically acceptable salts or isomers thereof. The inventionfurther relates to molecules which are useful in modulatingdysfunctional XPO1 activities and pharmaceutically acceptable salts,solvates, esters, or isomers thereof.

The invention is directed to compounds as described herein andpharmaceutically acceptable salts, solvates, esters, or isomers thereof,and pharmaceutical compositions comprising one or more compounds asdescribed herein and pharmaceutically acceptable salts or isomersthereof.

One aspect of this invention is the provision of compounds,compositions, kits, and antidotes for modulating XPO1 activities inmammals having a compound a compound having the structure of Formula(I′), Formula (II′) or Formula (III′):

-   -   a stereoisomer, an N-oxide, a solvate, a metabolite, a        pharmaceutically acceptable salt or a prodrug thereof, wherein,        -   R¹ is independently selected from —C(═O)—R², C₃₋₆            heterocycloalkyl, C₅₋₁₀ heteroaryl; any heterocycloalkyl or            heteroaryl of R¹ is optionally independently substituted            with one, or more substituents selected from the group            consisting of deuterium, —OH, —SH, —NO₂, halogen, amino,            cyano, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂            alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy and C₁₋₁₂            alkylsulfanyl; and        -   R² is independently selected from C₁₋₆ alkyl, C₃₋₆            cycloalkyl, C₃₋₆ heterocycloalkyl; any alkyl, cycloalkyl,            heterocycloalkyl of R² is optionally and independently            substituted with one or more substituents selected from the            group consisting of halogen, amino, cyano, C₁₋₁₂ alkyl,            C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl,            C₁₋₁₂ haloalkoxy and C₁₋₁₂ alkylsulfanyl; and        -   R³, R⁴ are independently selected from C₁₋₆ alkyl,            substituted C₁₋₆ alkyl, or R³ and R⁴ together with N which            they are attached form a substituted or unsubstituted C₄₋₁₀            cycloalkylamino; any alky or cycloalkylamino of R³ and R⁴ is            optionally and independently substituted with one or more            substituents selected from the group consisting of halogen,            amino, cyano, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,            C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy and C₁₋₁₂            alkylsulfanyl.

In one embodiment of the invention, the compound has the structure ofFormula (I′).

In another embodiment of the invention, the compound has the structureof Formula (II′), and the configuration of the double bond bearing R¹ iseither E or Z.

In still another embodiment of the invention, the compound has thestructure of Formula (III′).

In still another embodiment, the compound has the structure of Formula(I′); and R¹ is —C(═O)—R².

In yet another embodiment, R² is C₁₋₆ alkyl.

In yet another embodiment, R² is C₃₋₆ cycloalkyl.

In yet another embodiment, R² is substituted C₁₋₆ alkyl; and thesubstituent group is selected from methyl, hydroxyl, and halogen.

In yet another embodiment, R² is substituted C₃₋₆ cycloalkyl; and thesubstituent group is selected from methyl, hydroxyl, and halogen.

In still another embodiment, R² is selected from the group consisting ofmethyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, t-butyl,cyclobutyl, isobutyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl,3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, cyclopentenyl, andtetrahydrofuran,

more preferably, R² is selected from the group consisting of isopropyl,cyclopropyl, cyclobutyl, 4-methyl-2-pentyl, t-butyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl,

-   -   most preferably, R² is selected from the group consisting of        t-butyl, 2,2-dimethyl-1-butyl,

-   -   optionally, R² is selected from the group consisting of        2-methyloxiranyl, 2-methyl-1-butyl, 3-methyl-1-butyl,        2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl,        3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl,        3-methyl-2-pentyl, n-pentyl, isopentyl, neopentyl,        2,2-dimethylbutanyl, and

In still another embodiment, R¹ is C₃₋₆ heterocycloalkyl, of which oneor two of the carbon atoms is substituted with a nitrogen atom.

In some embodiments, R¹ is C₅₋₆ heteroaryl, of which one or two of thecarbon atoms is substituted with a nitrogen, or a sulfur atom.

In some embodiments, R¹ is C₆ heteroaryl, of which one or two of thecarbon atoms is substituted with a nitrogen atom; and the one or moresubstituent groups is selected from —NH₂, —OH, halogen and —CN.

In some embodiments, R¹ is selected from the group consisting ofunsubstituted or substituted

-   -   more preferably, R¹ is selected from the group consisting of        unsubstituted or substituted

-   -   optionally, R¹ is selected from the group consisting of        unsubstituted or substituted furyl, pyrrolyl, imdazolyl,        triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl,        thiazolyl, and thienyl.

In some embodiments, R¹ is substituted C₃₋₆ heterocycloalkyl, of whichone or two of the carbon atoms is substituted with a nitrogen atom; andthe one or more substituent groups is selected from halogen and —CN.

In some embodiments, R¹ is unsubstituted or substituted C₅₋₁₀heteroaryl, of which one or two of the carbon atoms is substituted witha nitrogen atom; and the one or more substituent groups is selected fromhalogen and —CN.

In some embodiments, R¹ is selected from the group consisting ofunsubstituted or substituted

-   -   more preferably, R¹ is unsubstituted or substituted

-   -   optionally, R¹ is selected from unsubstituted or substituted        phenyl, naphthyl, furyl, benzofuryl, pyrrolyl, imdazolyl,        benzimdazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl,        1,3,5-triazinyl, thiazolyl, thienyl, benzothienyl, indolyl,        purinyl, quinolyl, isoquinolyl and phenoxathiinyl

In some embodiments, the compound is a compound of Formula (I′); and R¹is —C(═O)—R².

In some embodiments, the compound is a compound of Formula (I′); and R¹is C₆ heteroaryl wherein one or two carbon atoms and the associatedhydrogen atom is replaced with a nitrogen atom.

In some embodiments, R³ and R⁴ are independently C₁₋₄ alkyl, or R³ andR⁴ together with N which they are attached from C₄₋₁₀ cycloalkylaminoring.

In some embodiments, R³ and R⁴ together with N which they are attachedto form a substituted C₄₋₁₀ cycloalkylamino; and the substituent groupis selected from the group consisting of methyl, ethyl, hydroxyl, andhalogen.

In some embodiments, R³ and R⁴ are joined together to form acycloalkylamino, wherein C₄₋₁₀ cycloalkylamino is selected from thegroup consisting of

In some embodiments, the compound is a compound of Formula (III′); R³and R⁴ together with N which they are attached form a substitutedcycloalkylamino, and the substituent group is selected from methyl,hydroxyl, and a halogen; and the one or more substituent groups ishalogen.

In some embodiments, the compound is selected from a compound of Formula(I′), Formula (II′), and Formula (III′).

In the following, the chemical nomenclature is based on ChemDrawProfessional 16.0.

In some embodiments, the compound is(Z)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(pyrazin-2-yl)acrylohydrazide.

In some embodiments, the compound is(Z)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(pyridin-2-yl)acrylohydrazide.

In some embodiments, the compound is(Z)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-pivaloylacrylohydrazide.

In some embodiments, the compound is(E)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(pyrimidin-5-yl)acrylamide.

In some embodiments, the compound is(Z)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(pyrimidin-5-yl)acrylamide.

In some embodiments, the compound is(Z)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(thiazol-2-yl)acrylohydrazide.

In some embodiments, the compound is(Z)—N′-(3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)cyclopropanecarbohydrazide.

In some embodiments, the compound is(Z)—N-isobutyryl-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide.

In some embodiments, the compound is(Z)—N-(3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)butyrohydrazide.

In some embodiments, the compound is(Z)—N-(3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)cyclobutanecarbohydrazide.

In some embodiments, the compound is(Z)-1-methyl-N-(3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)cyclopropane-1-carbohydrazide.

In some embodiments, the compound is(Z)—N-(3-chloro-2-(hydroxymethyl)-2-methylpropanoyl)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide.

In some embodiments, the compound is(Z)-3-methyl-N-(3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)butanehydrazide.

In some embodiments, the compound is(Z)—N-acetyl-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide.

In some embodiments, the compound is(Z)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-propionylacrylohydrazide.

In some embodiments, the compound is(Z)—N-(3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)cyclopentanecarbohydrazide.

In some embodiments, the compound is(Z)—N-(2-methyl-2-(methyl-d3)propanoyl-3,3,3-d3)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide.

In some embodiments, the compound is(Z)-3-(3-(3-(difluoromethyl)-5-(pentafluoro-sulfaneyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(pyrazin-2-yl)acrylohydrazide.

In some embodiments, the compound is(Z)-3-(3-(3-(difluoromethyl)-5-(pentafluoro-sulfaneyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(pyridin-2-yl)acrylohydrazide.

In some embodiments, the compound is(Z)-3-(3-(3-(difluoromethyl)-5-(pentafluoro-sulfaneyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-pivaloylacrylohydrazide.

In some embodiments, the compound is(Z)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(pyridazin-3-yl)acrylohydrazide.

In some embodiments, the compound is(Z)—N′-(2-hydroxy-2-methylpropanoyl)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide.

In some embodiments, the compound is(Z)—N-(2-fluoro-2-methylpropanoyl)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide.

In some embodiments, the compound is(Z)-1-hydroxy-N-(3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)cyclopropane-1-carbohydrazide.

In some embodiments, the compound is(Z)—N′-(3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)tetrahydrofuran-3-carbohydrazide.

In some embodiments, the compound is(Z)—N-(3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)tetrahydrofuran-2-carbohydrazide.

In some embodiments, the compound is(Z)-3-methyl-N-(3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)oxetane-3-carbohydrazide.

In some embodiments, the compound is(Z)-1-methyl-N-(3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)pyrrolidine-3-carbohydrazide.

In some embodiments, the compound is(E)-2-(2-fluoropyrimidin-5-yl)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylamide.

In some embodiments, the compound is(E)-2-(2-fluoropyridin-4-yl)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylamide.

In some embodiments, the compound is(E)-2-(5-cyanopyridin-3-yl)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylamide.

In some embodiments, the compound is(E)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(quinolin-3-yl)acrylamide.

Still another aspect of this invention is the provision of compounds,compositions, kits, and antidotes for modulating XPO1 activities inmammals, wherein such a compound is selected from the group consistingof:

I

(Z)-3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl)-N′- (pyrazin-2-yl) acrylohydrazide II

(Z)-3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl)-N′- (pyridin-2-yl) acrylohydrazide III

(Z)-3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl)-N′- pivaloyl- acrylohydrazide IV

(E)-3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl)- 2-(pyrimidin-5- yl)acrylamide V

(Z)-3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl)- 2-(pyrimidin-5- yl)acrylamide VI

(Z)-3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl)- N′-(thiazol-2-yl) acrylohydrazide VII

(Z)-N′-(3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)-1H- 1,2,4-triazol-1- yl)acryloyl) cyclopropane- carbohydrazideVIII

(Z)-N′- isobutyryl- 3-(3-(3- (pentafluoro- sulfaneyl)-5-(trifluoromethyl) phenyl)-1H- 1,2,4-triazol-1- yl) acrylohydrazide IX

(Z)-N′-(3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl) acryloyl) butyrohydrazide X

(Z)-N'-(3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1- yl)acryloyl) cyclobutane- carbohydrazide XI

(Z)-1-methyl- N-(3- (3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)- 1H-1,2,4-triazol- 1-yl)acryloyl) cyclopropane-1- carbohydrazideXII

(Z)-N′- (3-chloro-2- (hydroxymethyl)- 2-methyl- propanoyl)- 3-(3-(3-(pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)- 1H-1,2,4-triazol-1-yl) acrylohydrazide XIII

(Z)-3-methyl- N′-(3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)- 1H-1,2,4-triazol- 1-yl)acryloyl) butanehydrazide XIV

(Z)-N′-acetyl-3- (3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)- 1H-1,2,4-triazol- 1-yl) acrylohydrazide XV

(Z)-3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl)-N′- propionyl- acrylohydrazide XVI

(Z)-N′-(3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1- yl)acryloyl) cyclopentane- carbohydrazide XVII

(Z)-N′-(2-methyl- 2-(methyl- d3)propanoyl- 3,3,3-d3)-3-(3-(3-(pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl) acrylohydrazide XVIII

(Z)-3-(3-(3- (difluoromethyl)- 5-4 (pentafluoro- sulfaneyl) phenyl)-1H-1,2,4- triazol-1-yl)- N′-(pyrazin-2-yl) acrylohydrazide XIV

(Z)-3-(3-(3- (difluoromethyl)- 5-(pentafluoro- sulfaneyl) phenyl)-1H-1,2,4-triazol- 1-yl)- N′-(pyridin-2-yl) acrylohydrazide XV

(Z)-3-(3-(3- (difluoromethyl)- 5-4 (pentafluoro- sulfaneyl) phenyl)-1H-1,2,4-triazol- 1-yl)-N′- pivaloyl- acrylohydrazide XVI

(Z)-3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)-1H-1,2,4- triazol-1-yl)- N′-(pyridazin-3- yl) acrylohydrazideXVII

(Z)-N′-(2- hydroxy-2- methylpropanoyl)- 3-(3-(3- (pentafluoro-sulfaneyl)-5- (trifluoromethyl) phenyl)- 1H-1,2,4- triazol-1-yl)acrylohydrazide XVIII

(Z)-N′-(2- fluoro-2- methyl- propanoyl)- 3-(3-(3- (pentafluoro-sulfaneyl)-5- (trifluoromethyl) phenyl)- 1H-1,2,4- triazol-1-yl)acrylohydrazide XIX

(Z)-1-hydroxy- N′-(3-(3-(3- (pentafluoro- sulfaneyl)-5-(trifluoromethyl) phenyl)- 1H-1,2,4- triazol-1-yl) acryloyl)cyclopropane-1- carbohydrazide XX

(Z)-N′-(3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl) acryloyl) tetrahydrofuran- 3- carbohydrazide XXI

(Z)-N′-(3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl) acryloyl) tetrahydrofuran- 2- carbohydrazideXXII

(Z)-3-methyl- N′-(3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)- 1H-1,2,4-triazol- 1-yl)acryloyl) oxetane-3- carbohydrazideXXIII

(Z)-1-methyl- N′-(3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)-1H- 1,2,4-triazol- 1-yl)acryloyl) pyrrolidine-3- carbohydrazideXXIV

(E)-2-(2- fluoropyrimidin- 5-yl)-3-(3-(3- (pentafluoro- sulfaneyl)-5-(trifluoromethyl) phenyl)- 1H-1,2,4- triazol-1-yl) acrylamide XXV

(E)-2-(2- fluoropyridin- 4-yl)-3-(3-(3- (pentafluoro- sulfaneyl)-5-(trifluoromethyl) phenyl)- 1H-1,2,4- triazol-1-yl) acrylamide XXVI

(E)-2-(5- cyanopyridin- 3-yl)-3-(3-(3- (pentafluoro- sulfaneyl)-5-(trifluoromethyl) phenyl)- 1H-1,2,4- triazol-1-yl) acrylamide XXVII

(E)-3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl)- 2-(quinolin-3- yl)acrylamide

A compound provided by the present disclosure can have the structure ofFormula (I′):

-   -   or a pharmaceutically acceptable salt thereof, wherein R′ can be        selected from pyrazin-yl, pyrimidin-yl, pyridin-yl, thiazol-yl,        —C(═O)—R⁵ wherein R⁵ is selected from C₁₋₆ alkyl, C₃₋₅        cycloalkyl, —C(—CH₃)(—R⁶)₂ wherein each R⁶ is independently        selected from C₁₋₃ alkyl and substituted C₁₋₃ alkyl, or each R⁶        together with the geminal carbon atom form a C₃₋₆ cycloalkyl        ring.

In a compound of Formula (I′), each substituent is independentlyselected from, for example, —OH, —Cl, and C₁₋₄ alkyl.

In a compound of Formula (I′), R¹ can be pyrazin-yl,

In a compound of Formula (I′), R¹ can be pyrazin-2-yl.

In a compound of Formula (I′), R¹ can be pyrimidin-yl.

In a compound of Formula (I′), R¹ can be selected from pyrimidin-2-yl,pyrimidin-4-yl, and pyrimidin-5-yl.

In a compound of Formula (I′), R¹ can be pyridin-yl.

In a compound of Formula (I′), R¹ is selected from pyridin-2-yl,pyridin-3-yl, and pyridin-4-yl.

In a compound of Formula (I′), R¹ is thiazol-yl.

In a compound of Formula (I′), R¹ is thiazol-2-yl.

In a compound of Formula (I′), R¹ can be —C(═O)—R⁵.

In a compound of Formula (I′), R⁵ can be C₁₋₆ alkyl.

In a compound of Formula (I′), R⁵ can be selected from methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl.

In a compound of Formula (I′), R⁵ can be C₃₋₅ alkyl.

In a compound of Formula (I′), R⁵ can be selected from cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

In a compound of Formula (I′), R¹ can be —C(—CH3)(—R⁶)₂ wherein each R⁶can be independently selected from C₁₋₃ alkyl and substituted C₁₋₃alkyl.

In a compound of Formula (I′), each R⁶ can be independently selectedfrom —CH₂—R⁷.

In a compound of Formula (I′), each R⁷ can be independently selectedfrom, for example, —OH, —Cl, and C₁₋₄ alkyl.

In a compound of Formula (I′), each R⁶ together with the geminal carbonatom can form a C₃₋₆ cycloalkyl ring.

In a compound of Formula (I′), each R⁶ together with the geminal carbonatom can form a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring,or a cyclohexyl ring.

A compound provided by the present disclosure can have the structure ofFormula (II′):

-   -   or a pharmaceutically acceptable salt thereof, wherein R¹ can be        selected from pyrazin-yl, pyrimidin-yl, and pyridin-yl.

In a compound of Formula (II′), R¹ can be pyrazin-2-yl.

In a compound of Formula (II′), R¹ can be selected from pyrimidin-2-yl,pyrimidin-4-yl, and pyrimidin-5-yl.

In a compound of Formula (II′), R¹ can be selected from pyridin-2-yl,pyridin-3-yl, and pyridin-4-yl.

In a compound of Formula (II′), the double bond to which R¹ is bonded isin the E configuration.

In a compound of Formula (II′), the double bond to which R¹ is bonded isin the Z configuration.

A compound provided by the present disclosure can be(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(pyrimidin-5-yl)acrylamide(XXIV) having the structure:

An aspect of the present invention concerns compounds disclosed herein.

An aspect of the present invention concerns the preparation methods forcompounds disclosed herein.

In some embodiments, there provides a preparation method for certaincompounds having the general Formula (I′-III′) or certain compounds(I-XXVII) shown above, which comprises the steps of:

-   -   (a) providing a compound of Formula A:

-   -   wherein PG is halogen (Cl, Br, I), CN, N₃, NH₂, —COO—C₁₋₆ alkyl,        C₂₋₆ alkene, C₂₋₆ alkene-aryl.    -   (b) reacting said compound of formula A with an appropriate        reagent or reagents to form a compound of Formula B:

-   -   (c) reacting the reaction product according to Step (b) with a        compound of Formula C to form a compound of Formula D:

-   -   wherein, R¹ is defined above for the compound of Formula (I′),        (II′) or (III′).

In some embodiments, there provides a preparation method for preparingthe compound of Formula A, which comprises the steps of:

-   -   (a) providing a compound of Formula M:

-   -   (b) reacting said compound of formula M with suitable reagents        to form a compound of Formula N:

-   -   (c) reacting the reaction product according to Step (b) with        suitable reagents to form a compound of Formula J:

-   -   (d) reacting the reaction product according to Step (c) with        suitable reagents to form a compound of Formula K.

An aspect of the present invention concerns compounds which are or canbe modulators of dysfunctional XPO1 activities.

An aspect of the present invention concerns the use of a modulator ofdysfunctional XPO1 activities for the preparation of a medicament usedin the treatment, prevention, inhibition or elimination of tumors.

An aspect of the present invention concerns the use of a modulator ofdysfunctional XPO1 activities for the preparation of a medicament usedin the treatment, prevention, inhibition or elimination of a disorder ordisease or medical condition in a patient by modulating dysfunctionalXPO1 activities in said patient.

The present invention also describes one or more methods of synthesizingthe compounds of the present invention.

The invention also describes one or more uses of the compounds of thepresent invention.

The invention also describes one or more uses of the compounds of thepresent invention with an adjunctive agent such as use with tumornecrosis factor (TNF), granulocyte colony-stimulating factor (GCSF) orother chemotherapeutic agents.

The present invention also describes one or more methods of preparingvarious pharmaceutical compositions comprising the compounds of thepresent invention.

The invention also describes one or more uses of the variouspharmaceutical compositions of the present invention for the preparationof a medicament used in the treatment, prevention, inhibition orelimination of a disorder or disease or medical condition in a patientby modulating dysfunctional XPO1 activities in said patient.

The present invention provides a pharmaceutical composition comprisingcompounds of the present invention, e.g., example compounds. Accordingto the specific examples of the present invention, the pharmaceuticalcomposition can further comprise pharmaceutically acceptable excipient,carrier, adjuvant, solvent and a combination thereof.

The present invention provides a method of treating, preventing orameliorating a disease or disorder, comprising administrating a safe andeffective amount of a combination of drugs containing compounds of theinvention and one or more therapeutic active agents. Among them, thecombination of drugs comprises one or more additional drugs fortreatment of a cancer.

The amount of the compound of the pharmaceutical composition disclosedherein refers to an amount which can be effectively detected to modulatedysfunctional XPO1 activities of biology samples and in a patient. Theactive ingredient may be administered to subjects in need of suchtreatment in dosage that will provide optimal pharmaceutical efficacy,which is not limited to the desired therapeutic effects, on the route ofadministration, and on the duration of the treatment. The dosage willvary from patient to patient depending upon the nature and severity ofdisease, the patient's weight, special diet then being followed by apatient, concurrent medication, and other factors which those skilled inthe art will recognize. The quantity of active compound in a unit doseof preparation may be varied or adjusted from about 1 mg to about 1000mg, preferably from about 1 mg to about 500 mg, more preferably fromabout 1 mg to about 250 mg, still more preferably from about 1 mg toabout 50 mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required. Theamount and frequency of administration of the compounds of the inventionand/or the pharmaceutically acceptable salts thereof will be regulatedaccording to the judgment of the attending clinician considering suchfactors as age, condition and size of the patient as well as severity ofthe symptoms being treated. A typical recommended daily dosage regimenfor oral administration can range from about 1 mg/day to about 200mg/day, preferably 10 mg/day to 100 mg/day, which may be administered insingle or multiple doses. In yet another embodiment about 1 mg to 50 mgper patient per day.

It will also be appreciated that certain of the compounds of the presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative or a prodrug thereof. Apharmaceutically acceptable derivative includes pharmaceuticallyacceptable salts, esters, salts of such esters, or any other adduct orderivative which upon administration to a patient in need thereofprovide, directly or indirectly, a compound as otherwise describedherein, or an therapeutically effective metabolite or residue thereof.

The pharmaceutical compositions of the invention may be prepared andpackaged in bulk form wherein a safe and effective amount of a compoundof Formula (I-V) disclosed herein can be extracted and then given to thepatient, such as with powders or syrups. Generally, dosage levels ofbetween 0.0001 to 10 mg/kg of body weight daily are administered to thepatient to obtain effective modulation of dysfunctional XPO1 activities.Alternatively, the pharmaceutical compositions of the invention may beprepared and packaged in unit dosage form wherein each physicallydiscrete unit contains a safe and effective amount of a compound ofFormula (XPO1 activities) disclosed herein. When prepared in unit dosageform, the pharmaceutical compositions of the invention commonly containfrom about 0.5 mg to 1 g, or 1 mg to 700 mg, or 5 mg to 100 mg, or morepreferably, 25 mg to 60 mg of the compound of the invention.

When the pharmaceutical compositions of the present invention alsocontain one or more other active ingredients, in addition to a compoundof the present invention, the weight ratio of the compound of thepresent invention to the second active ingredient may be varied anddepend upon the effective dose of each ingredient. Thus, for example,when a compound of the present invention is combined with another agent,the weight ratio of the compound of the present invention to the otheragent will generally range from about 1000:1 to about 1:1000, such asabout 200:1 to 1:200. Combinations of a compound of the presentinvention and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient in the combination should be used.

“Pharmaceutically acceptable excipient” as used herein means apharmaceutically acceptable material, composition or vehicle involved ingiving form or consistency to the pharmaceutical composition. Eachexcipient must be compatible with the other ingredients of thepharmaceutical composition when commingled, such that interactions whichwould substantially reduce the efficacy of the compound of the inventionwhen administered to a patient and would result in pharmaceuticallyunacceptable compositions. In addition, each excipient must of course beof sufficiently high purity to render it pharmaceutically acceptable.

Suitable pharmaceutically acceptable excipients will vary depending uponthe particular dosage form chosen. In addition, suitablepharmaceutically acceptable excipients may be chosen for a particularfunction that they may serve in the composition. For example, certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of uniform dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of stable dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the carrying or transporting the compound of the presentinvention once administered to the patient from one organ, or portion ofthe body, to another organ, or portion of the body. Certainpharmaceutically acceptable excipients may be chosen for their abilityto enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the followingtypes of excipients: diluents, fillers, binders, disintegrants,lubricants, glidants, granulating agents, coating agents, wettingagents, solvents, co-solvents, suspending agents, emulsifiers,sweeteners, flavoring agents, flavor masking agents, coloring agents,anticaking agents, humectants, chelating agents, plasticizers, viscosityincreasing agents, antioxidants, preservatives, stabilizers,surfactants, and buffering agents. The skilled artisan will appreciatethat certain pharmaceutically acceptable excipients may serve more thanone function and may serve alternative functions depending on how muchof the excipient is present in the formulation and what otheringredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enablethem to select suitable pharmaceutically acceptable excipients inappropriate amounts for use in the invention. In addition, there areresources that are available to the skilled artisan that describepharmaceutically acceptable excipients and may be useful in selectingsuitable pharmaceutically acceptable excipients. Examples includeRemington's Pharmaceutical Sciences (Mack Publishing Company), TheHandbook of Pharmaceutical Additives (Gower Publishing Limited), and TheHandbook of Pharmaceutical Excipients (the American PharmaceuticalAssociation and the Pharmaceutical Press).

In Remington: The Science and Practice of Pharmacy, 21st edition, 2005,ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, andEncyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C.Boylan, 1988-1999, Marcel Dekker, New York, the contents of each ofwhich is incorporated by reference herein, are disclosed variouscarriers used in formulating pharmaceutically acceptable compositionsand known techniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention.

The pharmaceutical compositions of the invention are prepared usingtechniques and methods known to those skilled in the art. Some of themethods commonly used in the art are described in Remington'sPharmaceutical Sciences (Mack Publishing Company).

Therefore, another aspect of the present invention is related to amethod for preparing a pharmaceutical composition. The pharmaceuticalcomposition contains the compound disclosed herein and pharmaceuticallyacceptable excipient, carrier, adjuvant, vehicle or a combinationthereof, the method comprises mixing various ingredients. Thepharmaceutical composition containing the compound disclosed herein canbe prepared for example at normal ambient temperature and pressure.

The compound of the invention will typically be formulated into a dosageform adapted for administration to the patient by the desired route ofadministration. For example, dosage forms include those adapted for (1)oral administration such as tablets, capsules, caplets, pills, troches,powders, syrups, elixirs, suspensions, solutions, emulsions, sachets,and cachets; (2) parenteral administration such as sterile solutions,suspensions, and powders for reconstitution; (3) transdermaladministration such as transdermal patches; (4) rectal administrationsuch as suppositories; (5) inhalation such as aerosols, solutions, anddry powders; and (6) topical administration such as creams, ointments,lotions, solutions, pastes, sprays, foams, and gels.

The pharmaceutical compositions provided herein may be provided ascompressed tablets, tablet triturates, chewable lozenges, rapidlydissolving tablets, multiple compressed tablets, or enteric-coatingtablets, sugar-coated, or film-coated tablets. Enteric-coated tabletsare compressed tablets coated with substances that resist the action ofstomach acid but dissolve or disintegrate in the intestine, thusprotecting the active ingredients from the acidic environment of thestomach. Enteric coatings include, but are not limited to, fatty acids,fats, phenylsalicylate, waxes, shellac, ammoniated shellac, andcellulose acetate phthalates. Sugar-coated tablets are compressedtablets surrounded by a sugar coating, which may be beneficial incovering up objectionable tastes or odors and in protecting the tabletsfrom oxidation. Film-coated tablets are compressed tablets that arecovered with a thin layer or film of a water-soluble material. Filmcoatings include, but are not limited to, hydroxyethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycol 4000, and cellulose acetatephthalate. Film coating imparts the same general characteristics assugar coating. Multiple compressed tablets are compressed tablets madeby more than one compression cycle, including layered tablets, andpress-coated or dry-coated tablets.

The tablet dosage forms may be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein may be provided as softor hard capsules, which can be made from gelatin, methylcellulose,starch, or calcium alginate. The hard gelatin capsule, also known as thedry-filled capsule (DFC), consists of two sections, one slipping overthe other, thus completely enclosing the active ingredient. The softelastic capsule (SEC) is a soft, globular shell, such as a gelatinshell, which is plasticized by the addition of glycerin, sorbitol, or asimilar polyol. The soft gelatin shells may contain a preservative toprevent the growth of microorganisms. Suitable preservatives are thoseas described herein, including methyl- and propyl-parabens, and ascorbicacid. The liquid, semisolid, and solid dosage forms provided herein maybe encapsulated in a capsule. Suitable liquid and semisolid dosage formsinclude solutions and suspensions in propylene carbonate, vegetableoils, or triglycerides. Capsules containing such solutions can beprepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and4,410,545. The capsules may also be coated as known by those of skill inthe art to modify or sustain dissolution of the active ingredient.

The pharmaceutical compositions provided herein may be provided inliquid and semisolid dosage forms, including emulsions, solutions,suspensions, elixirs, and syrups. An emulsion is a two-phase system, inwhich one liquid is dispersed in the form of small globules throughoutanother liquid, which can be oil-in-water or water-in-oil. Emulsions mayinclude a pharmaceutically acceptable non-aqueous liquids or solvent,emulsifying agent, and preservative. Suspensions may include apharmaceutically acceptable suspending agent and preservative. Aqueousalcoholic solutions may include a pharmaceutically acceptable acetal,such as a di(lower alkyl)acetal of a lower alkyl aldehyde, e.g.,acetaldehyde diethyl acetal; and a water-miscible solvent having one ormore hydroxy groups, such as propylene glycol and ethanol. Elixirs areclear, sweetened, and hydroalcoholic solutions. Syrups are concentratedaqueous solutions of a sugar, for example, sucrose, and may also containa preservative. For a liquid dosage form, for example, a solution in apolyethylene glycol may be diluted with a sufficient quantity of apharmaceutically acceptable liquid carrier, e.g., water, to be measuredconveniently for administration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations may further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfate, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax, or the like.

The pharmaceutical compositions provided herein for oral administrationmay be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein may be provided asnon-effervescent or effervescent, granules and powders, to bereconstituted into a liquid dosage form. Pharmaceutically acceptablecarriers and excipients used in the non-effervescent granules or powdersmay include diluents, sweeteners, and wetting agents. Pharmaceuticallyacceptable carriers and excipients used in the effervescent granules orpowders may include organic acids and a source of carbon dioxide.

Coloring and flavoring agents can be used in all above dosage forms.

The compounds disclosed herein can also be coupled to soluble polymersas targeted medicament carriers. Such polymers may encompasspolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenolor polyethylene oxide polylysine, substituted by palmitoyl radicals. Thecompounds may furthermore be coupled to a class of biodegradablepolymers which are suitable for achieving controlled release of amedicament, for example polylactic acid, poly-epsilon-caprolactone,polyhydroxybutyric acid, polyorthoesters, polyacetals,polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathicblock copolymers of hydrogels.

The pharmaceutical compositions provided herein may be formulated asimmediate or modified release dosage forms, including delayed-,sustained, pulsed-, controlled, targeted-, and programmed-release forms.

The pharmaceutical compositions provided herein may be co-formulatedwith other active ingredients which do not impair the desiredtherapeutic action, or with substances that supplement the desiredaction.

The pharmaceutical compositions provided herein may be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, and subcutaneous administration.

The pharmaceutical compositions provided herein may be formulated in anydosage forms that are suitable for parenteral administration, includingsolutions, suspensions, emulsions, micelles, liposomes, microspheres,nanosystems, and solid forms suitable for solutions or suspensions inliquid prior to injection. Such dosage forms can be prepared accordingto conventional methods known to those skilled in the art ofpharmaceutical science (see, Remington: The Science and Practice ofPharmacy, supra).

The pharmaceutical compositions intended for parenteral administrationmay include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Non-aqueous vehicles include, but are not limited to, fixed oils ofvegetable origin, castor oil, corn oil, cottonseed oil, olive oil,peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Water-miscible vehiclesinclude, but are not limited to, ethanol, 1,3-butanediol, liquidpolyethylene glycol (e.g., polyethylene glycol 300 and polyethyleneglycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone,N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride(e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbicacid. Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfate and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsinclude those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80 and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to, EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, andsulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

The pharmaceutical compositions provided herein may be formulated forsingle or multiple dosage administration. The single dosage formulationsare packaged in an ampoule, a vial, or a syringe. The multiple dosageparenteral formulations must contain an antimicrobial agent atbacteriostatic or fungistatic concentrations. All parenteralformulations must be sterile, as known and practiced in the art.

In one embodiment, the pharmaceutical compositions are provided asready-to-use sterile solutions. In another embodiment, thepharmaceutical compositions are provided as sterile dry solubleproducts, including lyophilized powders and hypodermic tablets, to bereconstituted with a sterile vehicle prior to use. In yet anotherembodiment, the pharmaceutical compositions are provided as ready-to-usesterile suspensions. In yet another embodiment, the pharmaceuticalcompositions are provided as sterile dry insoluble products to bereconstituted with a vehicle prior to use. In still another embodiment,the pharmaceutical compositions are provided as ready-to-use sterileemulsions.

The pharmaceutical compositions may be formulated as a suspension,solid, semi-solid, or thixotropic liquid, for administration as animplanted depot. In one embodiment, the pharmaceutical compositionsprovided herein are dispersed in a solid inner matrix, which issurrounded by an outer polymeric membrane that is insoluble in bodyfluids but allows the active ingredient in the pharmaceuticalcompositions diffuse through.

Suitable inner matrixes include polymethylmethacrylate,polybutyl-methacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethylene terephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinyl acetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers, such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinyl alcohol, and cross-linked partiallyhydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinyl chloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer.

In other aspect, the pharmaceutical composition of the invention isprepared to a dosage form adapted for administration to a patient byinhalation, for example as a dry powder, an aerosol, a suspension, or asolution composition. In one embodiment, the invention is directed to adosage form adapted for administration to a patient by inhalation as adry powder. In one embodiment, the invention is directed to a dosageform adapted for administration to a patient by inhalation as a drypowder. Dry powder compositions for delivery to the lung by inhalationtypically comprise a compound disclosed herein or a pharmaceuticallyacceptable salt thereof as a finely divided powder together with one ormore pharmaceutically acceptable excipients as finely divided powders.Pharmaceutically acceptable excipients particularly suited for use indry powders are known to those skilled in the art and include lactose,starch, mannitol, and mono-, di-, and polysaccharides. The finelydivided powder may be prepared by, for example, micronization andmilling. Generally, the size-reduced (e.g., micronized) compound can bedefined by a D50 value of about 1 to about 10 microns (for example asmeasured using laser diffraction).

Aerosols may be formed by suspending or dissolving a compound disclosedherein or a pharmaceutically acceptable salt thereof in a liquifiedpropellant. Suitable propellants include halocarbons, hydrocarbons, andother liquefied gases. Representative propellants include:trichlorofluoromethane (propellant 11), dichlorofluoromethane(propellant 12), dichlorotetrafluoroethane (propellant 114),tetrafluoroethane (HFA-134a), 1,1-difluoroethane (HFA-152a),difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane(HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane,isobutane, and pentane. Aerosols comprising a compound of formula (A) ora pharmaceutically acceptable salt thereof will typically beadministered to a patient via a metered dose inhaler (MDI). Such devicesare known to those skilled in the art.

The aerosol may contain additional pharmaceutically acceptableexcipients typically used with MDIs such as surfactants, lubricants,cosolvents and other excipients to improve the physical stability of theformulation, to improve valve performance, to improve solubility, or toimprove taste.

Pharmaceutical compositions adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the patient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986).

Pharmaceutical compositions adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils. Ointments, creams andgels, may, for example, be formulated with an aqueous or oily base withthe addition of suitable thickening and/or gelling agent and/orsolvents. Such bases may thus, for example, include water and/or an oilsuch as liquid paraffin or a vegetable oil such as arachis oil or castoroil, or a solvent such as polyethylene glycol. Thickening agents andgelling agents which may be used according to the nature of the baseinclude soft paraffin, aluminum stearate, cetostearyl alcohol,polyethylene glycols, wool fat, beeswax, carboxypolymethylene andcellulose derivatives, and/or glyceryl monostearate and/or non-ionicemulsifying agents.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilizing agents,dispersing agents, suspending agents or thickening agents.

Powders for external application may be formed with the aid of anysuitable powder base, for example, talc, lactose or starch. Drops may beformulated with an aqueous or non-aqueous base also comprising one ormore dispersing agents, solubilizing agents, suspending agents orpreservatives.

Topical preparations may be administered via one or more applicationsper day to the affected area; over skin areas occlusive dressings mayadvantageously be used. Continuous or prolonged delivery may be achievedvia an adhesive reservoir system.

Compounds or pharmaceutical compositions of the invention disclosedherein can be used in the manufacture of a medicament for treating,preventing, ameliorating or mitigating a disorder or disease or a cancerin a subject, as well as other medicaments for modulating (e.g.,blocking) dysfunctional XPO1 activities, and the compounds of thisinvention have superior pharmacokinetic and pharmacodynamic properties,fewer toxic side-effect.

Specifically, the amount of the compound of compositions of the presentinvention can effectively and detectably modulate dysfunctional XPO1activities. The compounds or pharmaceutical compositions of theinvention may be used for preventing, treating or alleviating diseasesrelating to dysfunctional XPO1 activities.

A compound provided by the present disclosure can be used to treat aneurological disease or disorder such as, for example, amyotrophiclateral sclerosis, epilepsy, traumatic brain injuries, Huntington'sdisease, Parkinson's disease, rheumatoid arthritis, systemic lupuserythematosus.

A compound provided by the present disclosure can be used to treatcancer such as, for example, lymphoma, liposarcoma, multiple myeloma,myelodysplastic syndrome, prostate cancer, colorectal cancer,endometrial cancer, pancreatic cancer, gastric cancer, diffuse largeB-cell lymphoma, non-small cell lung cancer, ovarian carcinoma, breastcancer, acute myeloid leukemia, thymoma, esophageal cancer,glioblastoma, and other solid tumors.

A compound provided by the present disclosure can be used to treat acutelymphoblastic leukemia, acute myelogenous leukemia, acute myeloidleukemia, advanced thymic epithelial tumor, breast cancer, cervicalcarcinoma, chronic myeloid leukemia, colorectal neoplasm, coronavirusinfection, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma,endometrial carcinoma, gastric cancer, glioblastoma, glioma,hematological malignancies, leukemia, liposarcoma, melanoma, multiplemyeloma, myelodysplastic syndrome, neuroendocrine carcinoma, non-smallcell lung cancer, ovarian carcinoma, peripheral T-cell lymphoma,prostate cancer, solid tumors, squamous cell carcinoma, or thymoma.

In one embodiment, the therapies disclosed herein compriseadministrating a safe and effective amount of the compound of theinvention or the pharmaceutical composition containing the compound ofthe invention to patients in need. Each example disclosed hereincomprises the method of treating the diseases above comprisingadministrating a safe and effective amount of the compound of theinvention or the pharmaceutical composition containing the compound ofthe invention to patients in need.

In one embodiment, the compound of the invention or the pharmaceuticalcomposition thereof may be administered by any suitable route ofadministration, including both systemic administration and topicaladministration. Systemic administration includes oral administration,parenteral administration, transdermal administration and rectaladministration. Parenteral administration refers to routes ofadministration other than enteral or transdermal and is typically byinjection or infusion. Parenteral administration includes intravenous,intramuscular, and subcutaneous injection or infusion. Topicaladministration includes application to the skin as well as intraocular,intravaginal, inhaled and intranasal administration. In one embodiment,the compound of the invention or the pharmaceutical composition thereofmay be administered orally. In another embodiment, the compound of theinvention or the pharmaceutical composition thereof may be administeredby inhalation. In a further embodiment, the compound of the invention orthe pharmaceutical composition thereof may be administered intranasal.

In one embodiment, the compound of the invention or the pharmaceuticalcomposition thereof may be administered once or according to a dosingregimen wherein multiple doses are administered at varying intervals oftime for a given period of time. For example, doses may be administeredone, two, three, or four times per day. In one embodiment, a dose isadministered once per day. In a further embodiment, a dose isadministered twice per day. Doses may be administered until the desiredtherapeutic effect is achieved or indefinitely to maintain the desiredtherapeutic effect. Suitable dosing regimens for the compound of theinvention or the pharmaceutical composition thereof depend on thepharmacokinetic properties of that compound, such as its absorption,distribution, and half-lives of metabolism and elimination, which can bedetermined by the skilled artisan. In addition, suitable dosingregimens, including the duration such regimens are administered, for thecompound of the invention or the pharmaceutical composition thereofdepend on the disorder being treated, the severity of the disorder beingtreated, the age and physical condition of the patient being treated,the medical history of the patient to be treated, the nature ofconcurrent therapy, the desired therapeutic effect, and like factorswithin the knowledge and expertise of the skilled artisan. It will befurther understood by such skilled artisans that suitable dosingregimens may require adjustment given an individual patient's toleranceto the dosing regimen or over time as individual patient needs change.

The compounds of the present invention may be administered eithersimultaneously with, or before or after, one or more other therapeuticagents. The compounds of the present invention may be administeredseparately, by the same or different route of administration, ortogether in the same pharmaceutical composition as the other agents.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredients for asubject of about 50-70 kg, preferably about 1-500 mg or about 1-250 mgor about 1-150 mg or about 0.5-100 mg or about 1-50 mg of activeingredients. The therapeutically effective dosage of a compound, thepharmaceutical composition, or the combinations thereof, is dependent onthe species of the subject, the body weight, age and individualcondition, the disorder or disease or the severity thereof beingtreated. A physician, clinician or veterinarian of ordinary skill canreadily determine the effective amount of each of the active ingredientsnecessary to prevent, treat or inhibit the progress of the disorder ordisease.

The above-cited dosage properties can be correlated with in vitro and invivo tests using advantageously mammals, e.g., mice, rats, dogs,non-human primates, such as monkeys or isolated organs, tissues andpreparations thereof. The compounds of the present invention can beapplied in vitro in the form of solutions, e.g., preferably aqueoussolutions, and in vivo via topically, inhalation, enterally orparenterally, advantageously intravenously, e.g., as a suspension or inaqueous solution.

In one embodiment, a therapeutically effective dosage of the compounddisclosed herein from about 0.1 mg to about 1,000 mg per day. Thepharmaceutical compositions should provide a dosage of from about 0.1 mgto about 1,000 mg of the compound. In a special embodiment,pharmaceutical dosage unit forms are prepared to provide from about 1 mgto about 1,000 mg, about 10 mg to about 500 mg, about 20 mg to about 200mg, about 25 mg to about 100 mg, or about 30 mg to about 60 mg of theactive ingredient or a combination of essential ingredients per dosageunit form. In a special embodiment, pharmaceutical dosage unit forms areprepared to provide about 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 50 mg, 100mg, 250 mg, 500 mg, 1000 mg of the active ingredient.

The following examples are provided so that the invention might be morefully understood. However, it should be understood that theseembodiments merely provide a method of practicing the present invention,and the present invention is not limited to these embodiments.

Generally, the compounds disclosed herein may be prepared by methodsdescribed herein, wherein the substituents are as defined for Formula(I′-III′) above, except where further noted. The following non-limitingschemes and examples are presented to further exemplify the invention.

Professionals skilled in the art will recognize that the chemicalreactions described may be readily adapted to prepare a number of othercompounds disclosed herein, and alternative methods for preparing thecompounds disclosed herein are deemed to be within the scope disclosedherein. Those having skill in the art will recognize that the startingmaterials may be varied and additional steps employed to producecompounds encompassed by the present inventions, as demonstrated by thefollowing examples. In some cases, protection of certain reactivefunctionalities may be necessary to achieve some of the abovetransformations. In general, such need for protecting groups, as well asthe conditions necessary to attach and remove such groups, will beapparent to those skilled in the art of organic synthesis. For example,the synthesis of non-exemplified compounds according to the inventionmay be successfully performed by modifications apparent to those skilledin the art, e.g., by appropriately protecting interfering groups, byutilizing other suitable reagents known in the art other than thosedescribed, and/or by making routine modifications of reactionconditions. Alternatively, the known reaction conditions or the reactiondisclosed in the present invention will be recognized as havingapplicability for preparing other compounds disclosed herein.

In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Aldrich Chemical Company, ArcoChemical Company and Alfa Chemical Company, and were used withoutfurther purification unless otherwise indicated.

Preparation of Compounds

Compounds of the present invention, including salts, esters, hydrates,or solvates thereof, can be prepared using any known organic synthesistechniques and can be synthesized according to any of numerous possiblesynthetic routes.

The reactions for preparing compounds of the present invention can becarried out in suitable solvents, which can be readily selected by oneskilled in the art of organic synthesis. Suitable solvents can besubstantially non-reactive with the starting materials (reactants), theintermediates, or products at the temperatures at which the reactionsare carried out, e.g., temperatures that can range from the solvent'sfreezing temperature to the solvent's boiling temperature. A givenreaction can be carried out in one solvent or a mixture of more than onesolvent. Depending on the particular reaction step, suitable solventsfor a particular reaction step can be selected by a skilled artisan.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) (Preparative LC-MSPurification: Improved Compound Specific Method Optimization Karl F.Blom, Brian Glass, Richard Sparks, Andrew P. Combs, J. Combi. Chem.2004, 6(6), 874-883, which is incorporated herein by reference in itsentirety) and normal phase silica chromatography.

Compounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include but are not limitedto those methods described below. Specifically, the compounds of thepresent invention of Formula (A) can be synthesized by following thesteps outlined in the exemplary general synthetic schemes listed below,and the abbreviations for the reactants or for the chemical groups ofthe reactants included in the synthetic schemes are defined in theExamples.

The synthesis towards structure A1 can be conducted according to therelevant procedures disclosed in references (1, Chemistry—A EuropeanJournal, 2012, 18, 10234-10238; 2, WO2013/19548; 3, Bioorganic &Medicinal Chemistry, 2008, 16, 9487-9497; 4, Organic Letter, 2014, 16,4268-4271), but is not limited to these disclosed procedures. Wherein,PG is independently selected from halogen (Cl, Br, I), CN, N₃, NH₂,—COO—C₁₋₆ alkyl, C₂₋₆ alkene, C₂₋₆ alkene-aryl. Nitro compound 1-1 wasbrominated with NBS, and then reduced with ferrum to get intermediate1-2, which was further cyanided and iodinated to get compound 1-3. Thentrifluoromethyl group was added onto the aryl ring to get the importantintermediate compound A1.

There is an alternative method to synthesize the compound A2. Thesynthesis towards structure A2 can be conducted according to therelevant procedures disclosed in references (1, Chemistry—A EuropeanJournal, 2012, 18, 10234-10238; 2, WO2013/19548; 3, Bioorganic &Medicinal Chemistry, 2008, 16, 9487-9497; 4, Organic Letter, 2014, 16,4268-4271), but is not limited to these disclosed procedures. Nitrocompound 2-1 was brominated with NBS, and then reduced with ferrum toget intermediate 2-2, which was further cyanided and iodinated getcompound 2-3. Compound 3 was cyclized under acid condition to formtriazole compound 2-4, triphenylmethyl chloride (TACO was used toprotect the triazole amine group to form a stable compound 2-5.Copper-catalyzed trifluoromethylation method was used to theintroduction of the trifluoromethyl group into compound 2-6. After that,compound 2-6 was conjugated with olefin and amine or derivatives to getthe final product A2.

The synthesis towards structure A3 can be conducted according to therelevant procedures disclosed in references (1, WO2014205393; 2,Chemistry—A European Journal, 2012, 18, 1914-1917; 3, Journal ofMedicinal Chemistry, 1995, 38, 3287-3296), but is not limited to thesedisclosed procedures. Compound 3-1 was synthesized from scheme 1,following series of steps to get dibromide compound 3-2, and then removeone bromine to obtain olefin compound 3-3. Under Suzuki reactioncondition, varies of compound can be synthesized and amidated to get thefinal product A3.

Preparation and Characterization of Exemplary Compounds

Compounds encompassed in the present disclosure may be prepared viadifferent schemes. Detailed preparation processes of 10 exemplarycompounds via various schemes are described below and thecharacterization results are listed as well.

Unless stated otherwise, all reagents were purchased from commercialsuppliers without further purification. Solvent drying by standardmethods was employed when necessary. The plates used for thin-layerchromatography (TLC) were E. Merck silica gel 60F254 (0.24 nm thickness)precoated on aluminum plates, and then visualized under UV light (365 nmand 254 nm) or through staining with a 5% of dodecamolybdophosphoricacid in ethanol and subsequent heating. Column chromatography wasperformed using silica gel (200-400 mesh) from commercial suppliers. ¹HNMR spectra were recorded on an Agilent 400-MR NMR spectrometer (400.00MHz for 1 H) at room temperature. Solvent signal was used as referencefor ¹H NMR (CDCl₃, 7.26 ppm; CD₃OD, 3.31 ppm; DMSO-d₆, 2.50 ppm; D₂O,4.79 ppm). The following abbreviations were used to explain themultiplicities: s=singlet, d=doublet, t=triplet, q=quartet, br. s.=broadsinglet, dd=double doublet, td=triple doublet, dt=double triplet,dq=double quartet, m=multiplet. Other abbreviations used in theexperimental details are as follows: δ=chemical shift in parts permillion downfield from tetramethylsilane, Ar=aryl, Ac=acyl,Boc=tert-butyloxy carbonyl, Bn=Benzyl, DCM=dichloromethane,DMF=N,N′-dimethylformamide, DIPEA=diisopropylethylamine,DMAP=4-(dimethylamino)pyridine, DMSO=dimethyl sulphoxide, EA=ethylacetate, Et=ethyl, Me=methyl, Hz=hertz, HPLC=high performance liquidchromatography, J=coupling constant (in NMR), min=minute(s), h=hour(s),NMR=nuclear magnetic resonance, prep=preparative, t-Bu=tert-butyl,iPr=isopropyl, TBAF=tetrabutylammonium fluoride, tert=tertiary,TFA=trifluoroacetic acid, THF=tetrahydrofuran, TLC=thin-layerchromatography.

Aspects of the Invention

The invention is further defined by one or more of the followingaspects.

Aspect 1. A compound having the structure of Formula (I′), Formula (II′)or Formula (III′):

-   -   a stereoisomer, an N-oxide, a solvate, a metabolite, a        pharmaceutically acceptable salt or a prodrug thereof, wherein,        -   R¹ is selected from —C(═O)—R², C₃₋₆ heterocycloalkyl, C₅₋₁₀            heteroaryl; any heterocycloalkyl or heteroaryl of R¹ is            optionally independently substituted with one, or more            substituents selected from the group consisting of            deuterium, —OH, —SH, —NO2, halogen, amino, cyano, C₁₋₁₂            alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ alkoxy, C₁₋₁₂            haloalkyl, C₁₋₁₂ haloalkoxy and C₁₋₁₂ alkylsulfanyl; and        -   R² is selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₃₋₆            heterocycloalkyl; any alkyl, cycloalkyl, heterocycloalkyl of            R² is optionally and independently substituted with one or            more substituents selected from the group consisting of            halogen, amino, cyano, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂            alkynyl, C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy and            C₁₋₁₂ alkylsulfanyl; and        -   R³, R⁴ are independently selected from C₁₋₆ alkyl or R³ and            R⁴ together with N which they are attached form a            substituted or unsubstituted C₄₋₁₀ cycloalkylamino; any            alkyl or cycloalkylamino of R³ and R⁴ is optionally and            independently substituted with one or more substituents            selected from the group consisting of halogen, amino, cyano,            C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ alkoxy,            C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy and C₁₋₁₂ alkylsulfanyl.

Aspect 2. The compound of aspect 1, wherein the compound has thestructure of Formula (I′).

Aspect 3. The compound of aspect 1, wherein the compound has thestructure of Formula (II′), and the configuration of the double bondbearing R¹ is either E or Z.

Aspect 4. The compound of aspect 1, wherein the compound has thestructure of Formula (III′).

Aspect 5. The compound of aspect 1, wherein R¹ is —C(═O)—R².

Aspect 6. The compound of aspect 5, wherein R² is C₁₋₆ alkyl.

Aspect 7. The compound of aspect 5, wherein R² is C₃₋₆ cycloalkyl.

Aspect 8. The compound of aspect 5, wherein R² is substituted C₁₋₆alkyl; and the substituent group is selected from methyl, hydroxyl, anda halogen.

Aspect 9. The compound of aspect 5, wherein R² is substituted C₃₋₆cycloalkyl; and the substituent group is selected from methyl, hydroxyl,and a halogen.

Aspect 10. The compound of aspect 5, wherein R² is selected from thegroup consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl,n-butyl, t-butyl, cyclobutyl, isobutyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl,cyclopentenyl, and tetrahydrofuran,

-   -   more preferably, R² is selected from the group consisting of        isopropyl, cyclopropyl, cyclobutyl, 4-methyl-2-pentyl, t-butyl,        2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl,

-   -   most preferably, R² is selected from the group consisting of        t-butyl, 2,2-dimethyl-1-butyl,

-   -   optionally, R² is selected from the group consisting of        2-methyloxiranyl, 2-methyl-1-butyl, 3-methyl-1-butyl,        2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl,        3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl,        3-methyl-2-pentyl, n-pentyl, isopentyl, neopentyl,        2,2-dimethylbutanyl, and

Aspect 11. The compound of aspect 2, wherein R¹ is C₃₋₆heterocycloalkyl, of which one or two of the carbon atoms is substitutedwith a nitrogen atom.

Aspect 12. The compound of aspect 2, wherein R¹ is C₅₋₆ heteroaryl, ofwhich-one or two of the carbon atoms-is substituted with a nitrogen, ora sulfur atom.

Aspect 13. The compound of aspect 2, wherein R¹ is C₆ heteroaryl, ofwhich one or two of the carbon atoms is substituted with a nitrogenatom; and the one or more substituent groups is selected from —NH₂, —OH,halogen and —CN.

Aspect 14. The compound of aspect 2, wherein R¹ is selected from thegroup consisting of unsubstituted or substituted

-   -   more preferably, R¹ is selected from the group consisting of        unsubstituted or substituted

-   -   optionally, R¹ is selected from the group consisting of        unsubstituted or substituted furyl, pyrrolyl, imdazolyl,        triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl,        thiazolyl, and thienyl.

Aspect 15. The compound of aspect 2, wherein R¹ is substituted C₃₋₆heterocycloalkyl, of which one or two of the carbon atoms is substitutedwith a nitrogen atom; and the one or more substituent groups is selectedfrom halogen and —CN.

Aspect 16. The compound of aspect 3, wherein R¹ is unsubstituted orsubstituted C₅₋₁₀ heteroaryl, of which one or two of the carbon atoms issubstituted with a nitrogen, or a sulfur atom; and the one or moresubstituent groups is selected from halogen and —CN.

Aspect 17. The compound of aspect 16, wherein R¹ is selected from thegroup consisting of unsubstituted or substituted

more preferably, R¹ is unsubstituted or substituted

-   -   optionally, R¹ is selected from unsubstituted or substituted        phenyl, naphthyl, furyl, benzofuryl, pyrrolyl, imdazolyl,        benzimdazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl,        1,3,5-triazinyl, thiazolyl, thienyl, benzothienyl, indolyl,        purinyl, quinolyl, isoquinolyl and phenoxathiinyl

Aspect 18. The compound of aspect 1, wherein the compound is a compoundof Formula (I′); R¹ is —C(═O)—R².

Aspect 19. The compound of aspect 1, wherein the compound is a compoundof Formula (I′); R¹ is C₆ heteroaryl wherein one or two carbon atoms andthe associated hydrogen atom is replaced with a nitrogen atom.

Aspect 20. The compound of aspect 4, Wand R⁴ are independently C₁₋₄alkyl, or R³ and R⁴ together with N which they are attached from C₄₋₁₀cycloalkylamino ring.

Aspect 21. The compound of aspect 4, wherein R³ and R⁴ together with Nwhich they are attached form a substituted C₄₋₁₀ cycloalkylamino; andthe substituent group is selected from the group consisting of methyl,ethyl, hydroxyl, and halogen.

Aspect 22. The compound of aspect 4, wherein R³ and R⁴ are joinedtogether to form a cycloalkylamino, wherein C₄₋₁₀ cycloalkylamino isselected from the group consisting of

Aspect 23. The compound of aspect 1, wherein the compound is a compoundof Formula (III′); R³ and R⁴ together with N which they are attachedform a substituted cycloalkylamino, and the substituent group isselected from methyl, hydroxyl, and a halogen; and the one or moresubstituent groups is halogen.

Aspect 24. The compound of aspect 1, wherein the compound is selectedfrom a compound of Formula (I′), Formula (II′), and Formula (III′).

Aspect 25. A compound is selected from the group consisting of:

I

(Z)-3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)-1H-1,2,4- triazol-1-yl)- N′-(pyrazin-2-yl) acrylohydrazide II

(Z)-3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)-1H-1,2,4- triazol-1-yl)- N′-(pyridin-2-yl) acrylohydrazide III

(Z)-3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)-1H-1,2,4- triazol-1-yl)-N′- pivaloyl- acrylohydrazide IV

(E)-3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)-1H-1,2,4- triazol-1-yl)- 2-(pyrimidin-5- yl)acrylamide V

(Z)-3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)-1H-1,2,4- triazol-1-yl)- 2-(pyrimidin-5- yl)acrylamide VI

(Z)-3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)-1H-1,2,4- triazol-1-yl)- N′-(thiazol-2-yl) acrylohydrazide VII

(Z)-N′-(3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)-1H-1,2,4- triazol-1- yl)acryloyl) cyclopropane- carbohydrazideVIII

(Z)-N′-isobutyryl-3- (3-(3-(pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)- 1H-1,2,4-triazol-1- yl)acrylohydrazide IX

(Z)-N′-(3-(3-(3- (pentafluoro- sulfaneyl)- 5-(trifluoromethyl)phenyl)-1H-1,2,4- triazol-1-yl) acryloyl) butyrohydrazide X

(Z)-N′-(3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)-1H-1,2,4- triazol-1- yl)acryloyl) cyclobutane- carbohydrazide XI

(Z)-1-methyl-N′-(3- (3-(3-(pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)- 1H-1,2,4-triazol-1- yl)acryloyl) cyclopropane-1- carbohydrazideXII

(Z)-N′-(3-chloro-2- (hydroxymethyl)-2- methylpropanoyl)- 3-(3-(3-(pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl) acrylohydrazide XIII

(Z)-3-methyl-N′-(3- (3-(3-(pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)- 1H-1,2,4-triazol-1- yl)acryloyl) butanehydrazide XIV

(Z)-N′-acetyl-3- (3-(3-(pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)- 1H-1,2,4-triazol-1- yl)acrylohydrazide XV

(Z)-3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)-1H-1,2,4- triazol-1-yl)-N′- propionyl- acrylohydrazide XVI

(Z)-N′-(3-(3-(3- (pentafluoro- sulfaneyl)- 5-(trifluoromethyl)phenyl)-1H-1,2,4- triazol-1- yl)acryloyl) cyclopentane- carbohydrazideXVII

(Z)-N′-(2-methyl- 2-(methyl- d3)propanoyl- 3,3,3-d3)-3-(3-(3-(pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl) acrylohydrazide XVIII

(Z)-3-(3-(3- (difluoromethyl)-5- (pentafluoro- sulfaneyl)phenyl)- 1H-1,2,4-triazol-1-yl)- N′-(pyrazin-2- yl)acrylohydrazide XIV

(Z)-3-(3-(3- (difluoromethyl)-5- (pentafluoro- sulfaneyl)phenyl)- 1H-1,2,4-triazol-1-yl)- N′-(pyridin-2- yl)acrylohydrazide XV

(Z)-3-(3-(3- (difluoromethyl)-5- (pentafluoro- sulfaneyl) phenyl)-1H-1,2,4-triazol-1-yl)- N′- pivaloyl- acrylohydrazide XVI

(Z)-3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)-1H-1,2,4- triazol-1-yl)- N′-(pyridazin-3- yl)acrylohydrazideXVII

(Z)-N′-(2-hydroxy-2- methylpropanoyl)- 3-(3-(3- (pentafluoro-sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl)acrylohydrazide XVIII

(Z)-N′-(2-fluoro-2- methylpropanoyl)-3- (3-(3-(pentafluoro-sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl)acrylohydrazide XIX

(Z)-1-hydroxy- N′-(3-(3-(3- (pentafluoro- sulfaneyl)-5-(trifluoromethyl) phenyl)-1H-1,2,4- triazol-1- yl)acryloyl)cyclopropane-1- carbohydrazide XX

(Z)-N′-(3-(3-(3- (pentafluoro- sulfaneyl)- 5-(trifluoromethyl)phenyl)-1H-1,2,4- triazol-1- yl)acryloyl) tetrahydrofuran-3-carbohydrazide XXI

(Z)-N′-(3-(3-(3- (pentafluoro- sulfaneyl)- 5-(trifluoromethyl)phenyl)-1H-1,2,4- triazol-1- yl)acryloyl) tetrahydrofuran-2-carbohydrazide XXII

(Z)-3-methyl-N′-(3- (3-(3-(pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)- 1H-1,2,4-triazol-1- yl)acryloyl) oxetane- 3-carbohydrazideXXIII

(Z)-1-methyl-N′-(3- (3-(3-(pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)- 1H-1,2,4-triazol- 1-yl)acryloyl) pyrrolidine-3- carbohydrazideXXIV

(E)-2-(2- fluoropyrimidin- 5-yl)-3-(3-(3- (pentafluoro- sulfaneyl)-5-(trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl) acrylamide XXV

(E)-2-(2- fluoropyridin- 4-yl)-3-(3-(3- (pentafluoro- sulfaneyl)-5-(trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl) acrylamide XXVI

(E)-2-(5- cyanopyridin- 3-yl)-3-(3-(3- (pentafluoro- sulfaneyl)-5-(trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl) acrylamide XXVII

(E)-3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl)phenyl)-1H-1,2,4- triazol-1-yl)-2- (quinolin-3- yl)acrylamide

-   -   a stereoisomer, an N-oxide, a solvate, a metabolite, a        pharmaceutically acceptable salt or a prodrug thereof.

Aspect 26. A pharmaceutical composition comprising a therapeuticallyeffective amount of at least one compound according to any one of theproceeding aspects 1 to 25.

Aspect 27. The pharmaceutical composition of aspect 26, furthercomprising a pharmaceutically acceptable excipient, carrier, adjuvant,solvent, support or a combination any of the foregoing.

Aspect 28. The pharmaceutical composition of aspect 26, furthercomprising adjunctive therapies or therapeutically effective amounts ofone or more other adjunctive active ingredients or a combination any ofthe foregoing, wherein the other adjunctive active ingredients are usedfor treating a neurological disorder or a neurological disease or acancer.

Aspect 29. The pharmaceutical composition of aspect 28, wherein thetherapeutically effective amount of at least one compound is fortreating a disorder or disease associated with XPO1/CRM1 activity,comprising a neurological disorder or a neurological disease or acancer.

Aspect 30. The pharmaceutical composition of aspect 28, wherein thetherapeutically effective amount of at least one compound is fortreating a cancer, and the adjunctive therapies comprise radiation,while the adjunctive active ingredients comprise a chemotherapeuticagent, a TK or RTK inhibitor, a BCL2 inhibitor, a FLT3 inhibitor, a EGFRinhibitor, a pro-apoptotic drug, an antibody-drug conjugate (ADC), animmune checkpoint inhibitor, CAR-T, a personalized cancer vaccine, and achemokine/cytokine.

Aspect 31. The pharmaceutical composition of aspect 26, wherein thetherapeutically effective amount of at least one compound is fortreating a neurological disorder or a neurological disease.

Aspect 32. Use of the compound according to any one of aspects 1 to 25or the pharmaceutical composition according to any one of aspects 26 to31 in the manufacture of a medicament for treating or lessening adisorder or disease in a patient by modulating XPO1/CRM1 activity insaid patient.

Aspect 33. The use of the compound or pharmaceutical compositionaccording to aspect 32, wherein the disorder or disease is aneurological disorder or a neurological disease or a cancer.

Aspect 34. The compound according to any one of aspects 1 to 25 or thepharmaceutical composition according to any one of aspects 26 to 31 foruse in treating or lessening a disorder or disease in a human patient bymodulating XPO1/CRM1 activity in said patient.

Aspect 35. The compound or pharmaceutical composition for use accordingto aspect 34, wherein the disorder or disease is a neurological disorderor a neurological disease or a cancer.

Aspect 36. The compound or pharmaceutical composition for use accordingto aspect 34, wherein the disorder or disease is a neurological disorderor disease.

Aspect 37. The compound or pharmaceutical composition for use accordingto aspect 36, wherein the neurological disorder or disease isamyotrophic lateral sclerosis, epilepsy, traumatic brain injuries,Huntington's disease, Parkinson's disease, rheumatoid arthritis,systemic lupus erythematosus.

Aspect 38. The compound or pharmaceutical composition for use accordingto aspect 34, wherein the disorder or disease is a cancer.

Aspect 39. The compound or pharmaceutical composition for use accordingto aspect 38, wherein the cancer is lymphoma, liposarcoma, multiplemyeloma, myelodysplastic syndrome, prostate cancer, colorectal cancer,endometrial cancer, pancreatic cancer, gastric cancer, diffuse largeb-cell lymphoma, non-small cell lung cancer, ovarian carcinoma, breastcancer, acute myeloid leukemia, thymoma, esophageal cancer,glioblastoma, and other solid tumors.

Aspect 40. A method for treating or lessening a disorder or disease in apatient by modulating XPO1/CRM1 activity in said patient comprisingadministering to the patient a therapeutically effective amount of acompound according to any one of aspects 1 to 25 or a pharmaceuticalcomposition according to any one of aspects 26 to 31.

Aspect 41. The method of aspect 40, wherein the disorder or disease is aneurological disorder or disease.

Aspect 42. The method of aspect 41, wherein the neurological disorder ordisease is amyotrophic lateral sclerosis, epilepsy, traumatic braininjuries, Huntington's disease, Parkinson's disease, rheumatoidarthritis, systemic lupus erythematosus.

Aspect 43. The method of aspect 40, wherein the disorder or disease is acancer.

Aspect 44. The method of aspect 43, wherein the cancer is lymphoma,liposarcoma, multiple myeloma, myelodysplastic syndrome, prostatecancer, colorectal cancer, endometrial cancer, pancreatic cancer,gastric cancer, diffuse large b-cell lymphoma, non-small cell lungcancer, ovarian carcinoma, breast cancer, acute myeloid leukemia,thymoma, esophageal cancer, glioblastoma, and other solid tumors.

EXAMPLES

It should be noted that embodiments of the present invention describedin detail below are exemplary for explaining the present invention only,and not be construed as limiting the present invention. Examples withouta specific technology or condition can be implemented according totechnology or condition in the documentation of the art or according tothe product instructions. The reagents or instruments withoutmanufacturers are available through conventional purchase. Those havingskill in the art will recognize that the starting materials may bevarious and additional steps employed to produce compounds encompassedby the present inventions, as demonstrated by the following examples.

Example 1(Z)-3-(3-(3-(Pentafluorosulfanyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(pyrazin-2-yl)acrylohydrazide(I)

Step 1: Synthesis of Isopropyl Propiolate (2)

To a mixture of propiolic acid 1 (30 g, 0.43 moles) in isopropanol (100mL) was added BF₃ etherate (122.1 g, 0.86 moles) at 25° C. Afterstirring for 10 minutes, the reaction mixture was heated to 90° C. andstirred for 2 h. The completion of the reaction was monitored by TLC.The reaction mixture was brought down to 25 to 30° C. and quenched withcrushed ice followed by extracted with dichloromethane (2×150 mL). Theorganic layer was washed with water and then with brine solution.Organic layer was dried over Na₂SO₄ and concentrated under vacuum togive the isopropyl propiolate 2 (35.2 g, 73% yield).

Step 2: Synthesis of Isopropyl (Z)-3-Iodoacrylate (3)

Isopropyl propiolate 2 (35.2 g, 0.31 mmol) was added in acetic acid (200mL) at 25° C., and the reaction mixture was stirred for 10 minutes.Sodium iodide (70.0 g, 0.47 mmol) was added (a dark brown color wasobserved) while stirring. The temperature was increased to 110° C. andthe reaction was maintained at that temperature for 2 h. The completionof the reaction was monitored by TLC. The reaction mixture was cooled toroom temperature, quenched with ice cold water (200 mL) and stirred for30 minutes. Methyl tert-butyl ether (MTBE) (200 mL) was added to thereaction mixture and stirred for another 30 minutes. The organic layerwas separated, and the aqueous layer was re-extracted with MTBE (200mL). The combined organic layers were washed with NaHCO₃ (2×100 mL),NaHSO₃ (2×100 mL) and brine (100 mL), dried over Na₂SO₄ and concentratedunder vacuum at 35° C. to afford (Z)-isopropyl 3-iodoacrylate 3 (48.5 g,61% yield) as a light-yellow oil. 1H NMR (400 MHz, CDCl₃) δ 7.38 (d,J=8.0 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 5.07-5.13 (m, 1H), 1.27 (d, J=8.0Hz, 6H).

Step 3: Synthesis of (3-bromo-5-nitrophenyl)pentafluorosulfane (5)

To a 250 mL round-bottom flask was added compound 4 (9.25 g, 37.1 mmol),TFA (20 mL) and conc. H₂SO₄ (100 mL), then the mixture was stirredvigorously and NBS (9.92 g, 55.7 mmol) was added in portions over 30 minand the reaction was stirred at 25° C. for 12 h. The mixture was pouredinto ice water, extracted with EA (3×100 mL). The combined organic layerwas washed with saturated NaHCO₃ (3×100 mL) and water (3×100 mL), driedNa₂SO₄ and concentrated under vacuum. The crude product was purified onsilica gel column eluting with PE:EA=25:1 to obtain the titled compound5 (12.04 g, 99% yield) as a light-yellow oil. 1H NMR (400 MHz, CDCl₃) δ8.57 (s, 1H), 8.55 (s, 1H), 8.22 (s, 1H).

Step 4: Synthesis of 3-bromo-5-(pentafluorosulfanyl)aniline (6)

To a solution of compound 5 (5.9 g, 18.0 mmol) in MeOH (40 mL) and water(10 mL) was added and Fe (5.0 g, 90 mmol) and NH₄C₁ (4.8 g, 90 mmol) at25° C. The mixture was stirred at 90° C. for 2 h, and then filtered,washed with MeOH (20 mL) and removed the solvent. To the residue wasadded EA (100 mL) and washed with water (3×50 mL). The organic phase wasdried over Na₂SO₄ and concentrated under vacuum. The crude product waspurified on silica gel column eluting with PE:EA=10:1 to obtain thetitled compound 6 (5.1 g, 96% yield) as a light-yellow oil. 1H NMR (400MHz, CDCl₃) δ 7.35 (s, 1 H), 7.20 (s, 1H), 6.99 (s, 1H).

Step 5: Synthesis of 3-amino-5-(pentafluorosulfanyl)benzonitrile (7)

To a 250 mL round-bottom flask was added compound 6 (8.68 g, 29.2 mmol)and NMP (100 mL), then CuCN (5.26 g, 58.5 mmol) was added and thereaction was stirred at 180° C. under N₂ atmosphere for 6 h. The mixturewas cooled to 25° C. and filtered. To the filtrate was added EA (200 mL)and washed with water (3×200 mL). The organic layer was dried overNa₂SO₄ and concentrated under vacuum. The crude product was purified onsilica gel column with eluting solvent PE:EA=10:1 to obtain the titledcompound 7 (3.3 g, 46% yield) as a light yellow solid.

Step 6: Synthesis of 3-iodo-5-(pentafluorosulfanyl)benzonitrile (8)

Compound 7 (4.23 g, 17.3 mmol) was suspended in a mixture of conc. H2504(8.7 mL) and water (17.3 mL) and cooled to 0° C. A solution of NaNO₂(1.23 g, 17.9 mmol) in H₂O (3.5 mL) was added over 1 h and the resultingmixture was stirred further for 1 h at 0° C. Then CuI (173 mg, 0.87mmol), KI (3.05 g, 18 mmol) in H₂O (3.5 mL) was added dropwise over 1 h,then the mixture was stirred at 25° C. for 10 h. To the mixture wasadded EA (100 mL) and washed with H₂O (3×50 mL). The organic layer wasdried over Na₂SO₄ and concentrated under vacuum. The crude product waspurified on silica gel column with eluting solvent PE:EA=5:1 to obtainthe titled compound 8 (3.65 g, 59% yield) as a light yellow solid. ¹HNMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 8.13 (s, 1H), 8.01 (s, 1H).

Step 7: Synthesis of 3-iodo-5-(pentafluorosulfanyl)benzothioamide (9)

To a solution of compound 8 (3.6 g, 10 mmol) in DMF (50 mL) was addedNaHS (1.1 g, 20 mmol) and MgCl₂·6H₂O (2 g, 10 mmol), the mixture wasstirred at 25° C. for 2 h. To the mixture was added EA (100 mL) andwashed with H₂O (3×50 mL). The organic layer was dried over Na₂SO₄ andconcentrated under vacuum to obtain a crude product 9 (3.8 g, 98% yield)which was used for next step without any purification. MS (ESI):[M+H⁺]=389.9.

Step 8: Synthesis of 3-(3-iodo-5-(pentafluorosulfanyl)phenyl)-1H-1, 2,4-triazole (10)

To a solution of compound 9 (3.32 g, 8.53 mmol) in DMF (15 mL) was addedN₂H₄·H₂O (853 mg, 17.1 mmol), the mixture was stirred at 25° C. for 3 h.Then formic acid (10 mL) was added and the mixture was stirred at 90° C.for 3 h. The reaction was cooled to 25° C. and quenched with saturatedNaHCO₃ (50 mL), extracted with EA (50 mL). The organic layer was washedwith brine (50 mL), dried over Na₂SO₄ and concentrated under vacuum toobtain a crude product 10 (3.36 g, 99% yield) which was used for nextstep without further purification. nMS (ESI): [M+H⁺]=397.9.

Step 9: Synthesis of3-(3-iodo-5-(pentafluorosulfanyl)phenyl)-1-trityl-1H-1,2,4-triazole (11)

To a solution of compound 10 (3.37 g, 8.53 mmol) in DCM (50 mL) wasadded Et₃N (1.29 g, 12.8 mmol) and TrtCl (3.57 g, 12.8 mmol), themixture was stirred at 25° C. for 2 h then washed with water (3×50 mL).The organic layer was dried and concentrated under vacuum. The crudeproduct was purified on silica gel column with eluting solventDCM:MeOH=50:1 to obtain the titled compound 11 (5.36 g, 98% yield) as alight yellow solid. 1H NMR (400 MHz, CDCl₃) δ 8.57 (s, 1H), 8.46 (s,1H), 8.05 (s, 1H), 8.01 (s, 1H), 7.37-7.15 (m, 15H).

Step 10: Synthesis of3-(3-(pentafluorosulfanyl)-5-(trifluoromethyl)phenyl)-1-trityl-1H-1, 2,4-triazole (12)

To a 100 mL three-neck flask was charged with compound 11 (5.36 g, 8.4mmol), KF (1.46 g, 25.2 mmol), CuI (320 mg, 1.7 mmol),1,10-phenanthroline (306 mg, 1.7 mmol), then the crude material in flaskwas vacuum for three times under N₂ atmosphere. Then a mixture solutionof DMSO (20 mL) and DMF (10 mL), TMSCF₃ (4.76 g, 33.6 mmol) and B(OMe)₃(2.55 g, 25.2 mmol) was added to above reaction solution, then thereaction was stirred at 70° C. under N₂ atmosphere for 24 h. The mixturewas cooled to 25° C. and filtered. To the filtrate was added EA (100 mL)and washed with H₂O (3×50 mL) and brine (3×50 mL). The organic layer wasdried over Na₂SO₄ and concentrated under vacuum to obtain the titledcompound 12 (4.88 g, 99% yield) as a black solid which was used for nextstep without any purification. 19F NMR (400 MHz, CDCl₃) δ 62.45 ppm,−62.79 ppm.

Step 11: Synthesis of3-(3-(pentafluorosulfanyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazole(13)

To a solution of compound 12 (4.88 g, 8.4 mmol) in DCM (50 mL) was addedTFA (1.67 g, 14.3 mmol) and Et₃SiH (1.95 g, 16.8 mmol), the mixture wasstirred at 25° C. for 1 h then concentrated under vacuum to remove theorganic solution. To the residue was added EA (100 mL) and washed withH₂O (3×50 mL). The organic layer was dried over Na₂SO₄ and concentratedunder vacuum. The crude product was purified on silica gel columneluting with PE:EA=1:1 to obtain the titled compound 13 (2.1 g, 74%yield) as a light yellow solid. MS (ESI): [M+H⁺]=340.1.

Step 12: Synthesis of isopropyl(Z)-3-(3-(3-(pentafluorosulfanyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylate(14)

To a solution of compound 13 (2.1 g, 6.2 mmol) in DMF (15 mL) was addedDABCO (1.39 g, 12.4 mmol) and compound 3 (2.08 g, 8.7 mmol), the mixturewas stirred at 25° C. for 3 h then quenched with saturated NH₄Cl (50mL), extracted with EA (100 mL). The organic layer was washed with brine(3×50 mL), dried over Na₂SO₄, filtered and concentrated under vacuum.The crude product was purified on silica gel column eluting withPE:EA=30:1 to obtain the titled compound 14 (2.09 g, 75% yield) as awhite solid. MS (ESI): [M+H⁺]=452.1. ¹H NMR (400 MHz, CDCl₃) δ 8.64 (s,1H), 8.51 (s, 1H), 8.34 (s, 1H), 8.11 (s, 1H), 7.96 (d, J=14.1 Hz, 1H),7.69 (d, J=13.7 Hz, 1H), 5.15 (m, 1H), 1.32 (d, J=6.3 Hz, 6H).

Step 13: Synthesis of(Z)-3-(3-(3-(pentafluorosulfanyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylicacid (15)

To a solution of compound 14 (2.09 g, 4.63 mmol) in THF (20 mL) wasadded LiOH H₂O (3.34 g, 55.6 mmol, 1N in 56 mL H₂O), the mixture wasstirred at 25° C. for 3 h and then acidified with 1 N HCl to pH=3,extracted with EA (3×100 mL). The organic layer was washed withsaturated NaHCO₃ (50 mL), dried over Na₂SO₄ and concentrated undervacuum to obtain the titled compound 15 (1.89 g, 99% yield) as a whitesolid. MS (ESI): [M+H⁺]=410.0.

Step 14: Synthesis of(Z)-3-(3-(3-(pentafluorosulfanyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(pyrazin-2-yl)acrylohydrazide(I)

To a solution of compound 15 (1.01 g, 2.5 mmol), 16 (826 mg, 7.5 mmol),DIEA (1.29 g, 10 mmol) in EA/DCM (10 mL/10 mL, v/v) was added T3P (6.36g, 10 mmol, 50% in EA). The mixture was stirred at −40° C. for 3 h, thenthe organic solution was concentrated under vacuum. To the residue wasadded EA (100 ml) and washed with H₂O (3×50 mL). The organic phase wasconcentrated and purified by prep-TLC (DCM:MeOH:NH₃·H₂O=15:1:0.1) toobtain the titled compound I (594 mg, 48% yield) as a yellow solid. MS(ESI): [M+H⁺]=502.1. ¹H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 9.56 (s,1H), 9.11 (s, 1H), 8.61 (s, 1H), 8.48 (s, 1H), 8.39 (s, 1H), 8.07 (s,2H), 7.90 (s, 1H), 7.50 (d, J=10 Hz, 1H), 6.06 (d, J=10.4 Hz, 1H).

Example 2(Z)-3-(3-(3-(Pentafluorosulfanyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(pyridin-2-yl)acrylohydrazide(II)

Step 1:(Z)-3-(3-(3-(Pentafluorosulfanyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(pyridin-2-yl)acrylohydrazide(II)

To a solution of compound 15 (40 mg, 0.1 mmol), 2-hydrazineylpyridine(32 mg, 0.3 mmol), DIEA (52 mg, 0.4 mmol) in EA:DCM (1 mL:1 mL) wasadded T3P (190 mg, 0.3 mmol, 50% in EA). The mixture was stirred at −40°C. for 3 h, then the organic solution was concentrated under vacuum. Tothe residue was added EA (50 mL) and washed with H₂O (3×50 mL). Theorganic phase was concentrated and purified by prep-TLC(DCM:MeOH:NH₃·H₂O=15:1:0.1) to obtain the titled compound II (23 mg, 46%yield) as a yellow solid. After that, the product was formed withHCl/Dioxane solution to get a solid product. MS (ESI): [M+H⁺]=501.1. ¹HNMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 9.52 (s, 1H), 8.62 (s, 1H), 8.49(s, 1H), 8.41 (s, 1H), 8.02 (m, 2H), 7.63 (d, J=10.4 Hz, 1H), 7.20 (m,1H), 7.04 (m, 1H), 6.12 (d, J=10.5 Hz, 1H).

Example 3 (Z)-3-(3-(3-(Pentafluorosulfanyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-pivaloylacrylohydrazide(III)

Step 1:(Z)-3-(3-(3-(Pentafluorosulfanyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylicacid (15)

To a stirred solution of compound 14 (150 mg, 0.33 mmol) in dry THF (15mL) was added a solution of LiOH (2.6 mL, 2.64 mmol, 1 M) dropwise at 0°C. The reaction was stirred at 25° C. for 3 h. After that, the reactionmixture was quenched with HCl (1 M) until pH=2-3, extracted with EA(3×20 mL). The organic layer was washed with brine (40 mL), dried overNa₂SO₄ and concentrated to give compound 15 (125 mg, 92% yield) as awhite solid. MS (ESI):[M+H]⁺=409.9.

Step 2:(Z)-3-(3-(3-(Pentafluorosulfanyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-pivaloylacrylohydrazide(III)

To a stirred solution of compound 15 (125 mg, 0.31 mmol) in DCM:EA (5mL:5 mL, v/v) was cooled to −78° C. and added pivalohydrazide (54.0 mg,0.46 mmol), DIEA (80.0 mg, 0.62 mmol) and T3P (395 mg, 0.62 mmol, 50 wt% in EA) at 0° C. The reaction was stirred at 25° C. for 3 h, and thenquenched with saturated ammonium chloride (20 mL). The mixture wasextracted with DCM and the organic layer washed with brine, dried overNa₂SO₄ and concentrated under vacuum to afford crude white solid. Thesolid was added to MeCN (5 mL) and stirred for 2 h at 25° C. and thenfiltrated, washed with MeCN (10 mL) to give the titled product III (110mg, 69% yield) as a white solid. MS (ESI):[M+H]⁺=506.9. ¹H NMR (400 MHz,DMSO-d6) δ 10.41 (s, 1H), 9.66 (d, J=8 Hz, 2H), 8.66 (s, 1H), 8.56 (s, 1H), 8.43 (s, 1H), 7.49 (d, J=10.8 Hz, 1H), 6.04 (d, J=10.4 Hz, 1H), 1.17(s, 9H).

Example 4(E)-3-(3-(3-(Pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(pyrimidin-5-yl)acrylamide(IV)

Step 1: Synthesis of isopropyl2,3-dibromo-3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)propanoate(20)

To a solution of compound 14 (9.0 g, 20 mmol) in DCM (60 mL) was addedBr₂ (6.31 g, 40 mmol) at 0° C. then the mixture was stirred at 25° C.for 10 h. The mixture was washed with H₂O (3×60 mL) and saturatedNa₂S₂O₃ (60 mL). The organic solution was dried over Na₂SO₄, filteredand concentrated to obtain 12.2 g (99% yield) of compound 20 as a yellowsolid. MS (ESI): [M+H]⁺=611.9.

Step 2: Synthesis of isopropyl(Z)-2-bromo-3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylate(21)

To a stirred solution of compound 20 (12.2 g, 20 mmol) in THF (120 mL)was added a solution of lithium hydroxide hydrate (13 mL, 40 mmol, 3 Min H₂O) dropwise at −20° C. The reaction was stirred at −20° C. for 2.5h. After that, the reaction mixture was quenched with HCl (1M) untilpH=4, and then extracted with EA (200 mL). The organic layer was washedwith H₂O (3×100 mL) and brine (3×100 mL), dried over Na₂SO₄, filteredand concentrated to give crude product 10.6 g (99% yield) of compound 21as a yellow solid. MS (ESI): [M+H]⁺=529.9. ¹H NMR (400 MHz, CDCl₃) δ9.47 (s, 1H), 8.76 (s, 1H), 8.75 (s, 1H), 8.59 (s, 1H), 8.07 (s, 1H),5.25-5.19 (m, 1H), 1.39 (d, J=8 Hz, 6H).

Step 3: Synthesis of isopropyl(E)-3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(pyrimidin-5-yl)acrylate(22)

To a solution of compound 21 (1.06 g, 2 mmol) and pyrimidin-5-ylboronicacid (397 mg, 3.2 mmol) in dioxane:H₂O (10 mL:3 mL) was added Pd(PPh₃)₄(231 mg, 0.2 mmol) and Cs₂CO₃ (1.3 g, 4 mmol) under nitrogen atmosphereat 25° C. The reaction mixture was stirred at 85° C. under a nitrogenatmosphere for 4 h, cooled to 25° C. and the organic solution wasconcentrated. To the residue was added EA (200 mL) and the residue wasthen washed with H₂O (3×100 mL), and the organic solution was dried overNa₂SO₄, filtered and concentrated. The crude product was purified on asilica gel column (PE:EA=2:1) to obtain 603 mg (57% yield) of compound22 as a white solid. MS (ESI): [M+H]⁺=530.1. ¹H NMR (400 MHz, DMSO-d6) δ9.26 (s, 1H), 9.19 (s, 1H), 8.78 (s, 2H), 8.68 (s, 1H), 8.38 (s, 1H),8.13 (s, 1H), 8.09 (s, 1H), 5.13-5.07 (m, 1H), 1.27 (d, J=8 Hz, 6H).

Step 4: Synthesis of(E)-3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(pyrimidin-5-yl)acrylicacid (23)

To a solution of compound 22 (1.16 g, 2.2 mmol) in DCM (100 mL) wasadded AlCl₃ (1.2 g, 8.8 mmol) at 0° C. Then the reaction mixture wasstirred at 25° C. for 2.5 h and then warmed to 30° C. and stirred atthis temperature for 0.5 h. The reaction was quenched with H₂O (15 mL)and the organic solution was concentrated. To the residue was added EA(100 mL) which was then washed with H₂O (3×100 mL) and HCl solution (30mL, 1N). The organic solution was dried over Na₂SO₄, filtered andconcentrated. The crude product was purified on a silica gel column(DCM:MeOH:AcOH=10:1:0.1, v/v) to obtain 684 mg (64% yield) of compound23 as a white solid. MS (ESI): [M+H]⁺=487.9.

Step 5: Synthesis of(E)-3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(pyrimidin-5-yl)acrylamide(IV)

To a stirred solution of compound 23 (684 mg, 1.4 mmol) in dry THF (30mL) was added NMM (283 mg, 2.8 mmol) and isopropyl carbonochloridate(346 mg, 2.8 mmol) dropwise at 0° C. The reaction was stirred at 0° C.for 20 mins. After that, a solution of NH₄OH (294 mg, 8.4 mmol) wasadded to the mixture at 0° C., and the mixture was stirred another 5mins at 25° C., and then quenched with H₂O (50 mL), and the organicsolution was concentrated. To the residue was added EA (100 mL) and thenwashed with H₂O (3×100 mL). The organic layer was dried over Na₂SO₄ andconcentrated. The residue was purified on silica gel column by elutingwith EA to obtain 480 mg (71% yield) of Compound IV as a white solid. MS(ESI): [M+H]⁺=486.9. ¹H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 9.14 (s,1H), 8.72 (s, 2H), 8.42 (s, 1H), 8.36 (s, 1H), 8.13 (s, 1H), 8.09 (s,1H), 7.63 (s, 1H), 7.39 (s, 1H).

Example 5(Z)-3-(3-(3-(Pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(pyrimidin-5-yl)acrylamide(V)

Step 1: Synthesis of isopropyl (E)-2,3-diiodoacrylate (26)

To a stirred solution of compound 25 (336 mg, 3 mmol) in CH₃CN (5 mL)was added CuI (29 mg, 0.15 mmol) and 12 (1.14 g, 4.5 mmol) at 25° C. Thereaction was stirred at 80° C. for 8 h. After that, MTBE (20 mL) wasadded to the mixture, and the mixture was washed with H₂O (3×20 mL) andsaturated Na₂S₂O₃ solution (3×20 mL). The organic layer was dried overNa₂SO₄ and concentrated. The residue was purified on silica gel columnby eluting with PE:EA (5:1) to obtain 453 mg (41% yield) of compound 26as a light-yellow oil. 1H NMR (400 MHz, CDCl₃) δ 7.61 (s, 1H), 5.19-5.10(m, 1H), 1.36 (d, J=6.4 Hz, 6H).

Step 2: Synthesis of isopropyl(E)-2-iodo-3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylate(27) and isopropyl(Z)-2-iodo-3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylate(28)

To a solution of compound 13 (780 mg, 2.3 mmol) in DMF (10 mL) was addedDABCO (515 mg, 4.6 mmol) and compound 26 (1.68 g, 4.6 mmol) at 0° C.,the mixture was stirred at 80° C. for 0.5 h, quenched with saturatedNH₄C₁ (50 mL), and extracted with EA (100 mL). The organic layer waswashed with brine (3×50 mL), dried, filtered and concentrated. The crudeproduct was purified on a silica gel column by eluting with PE:EA (5:1)to obtain the titled compound 27 (1.1 g, 83% yield) as a white solid; MS(ESI): [M+H]⁺=577.9. ¹H NMR (400 MHz, CDCl₃) δ 8.67 (s, 1H), 8.52 (s,2H), 8.04 (s, 1H), 7.57 (s, 1H), 5.22-5.16 (m, 1H), 1.34 (d, J=8 Hz,6H); and compound 28 (210 mg, 16% yield) as a white solid; MS (ESI):[M+H]⁺=577.9; 1H NMR (400 MHz, CDCl₃) δ 9.52 (s, 1H), 8.81 (s, 1H), 8.75(s, 1H), 8.59 (s, 1H), 8.07 (s, 1H), 5.23-5.17 (m, 1H), 1.38 (d, J=8 Hz,6H).

Step 3: Synthesis of isopropyl(Z)-3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(pyrimidin-5-yl)acrylate(29) and isopropyl(E)-3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(pyrimidin-5-yl)acrylate(30)

To a solution of compound 27 (58 mg, 0.1 mmol) and pyrimidin-5-ylboronicacid (20 mg, 0.16 mmol) in dioxane:H₂O (3 mL:1 mL) was added Pd(dppf)Cl₂(8 mg, 0.01 mmol) and K2CO3 (28 mg, 0.2 mmol) under a nitrogenatmosphere at 25° C. The reaction mixture was stirred at 50° under anitrogen atmosphere for 2 h, cooled to 25° C., and the organic solutionwas concentrated. To the residue was added EA (50 mL) which was thenwashed with H₂O (3×50 mL). The organic solution was dried over Na₂SO₄,filtered and concentrated. The crude product was purified on a silicagel column (PE:EA=2:1) to obtain the titled compound 29 (24 mg, 46%yield) as a white solid′ MS (ESI): [M+H]⁺=530.1; 1H NMR (400 MHz,DMSO-d6) δ 9.21 (s, 1H), 9.02 (s, 1H), 8.92 (s, 2H), 8.59 (s, 1H), 8.47(s, 1H), 8.43 (s, 1H), 8.19 (s, 1H), 5.21-5.16 (m, 1H), 1.25 (d, J=8 Hz,6H); and compound 30 (12 mg, 23% yield) as a white solid; MS (ESI):[M+H]⁺=530.1; ¹H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 9.19 (s, 1H),8.78 (s, 2H), 8.68 (s, 1H), 8.38 (s, 1H), 8.13 (s, 1H), 8.09 (s, 1H),5.13-5.07 (m, 1H), 1.27 (d, J=8 Hz, 6H).

Step 4: Synthesis of(Z)-3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(pyrimidin-5-yl)acrylicacid (31)

To a solution of compound 28 (20 mg, 2.2 mmol) in DCM (3 mL) was addedAlCl₃ (21 mg, 0.16 mmol) at 0° C. Then the reaction mixture was stirredat 35° C. for 4 h. The reaction was quenched with H₂O (5 mL) and theorganic solution was concentrated. To the residue was added EA (10 mL),which was then washed with H₂O (3×10 mL) and HCl solution (10 mL, 1N).The organic solution was dried over Na₂SO₄, filtered and concentrated.The crude product was purified on a silica gel column(DCM:MeOH:AcOH=10:1:0.1, v/v) to obtain 10 mg (56% yield) of compound 31as a white solid. MS (ESI): [M+H]⁺=487.9.

Step 5: Synthesis of(Z)-3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(pyrimidin-5-yl)acrylamide(V)

To a stirred solution of compound 31 (10 mg, 0.02 mmol) in dry THF (2mL) was added NMM (4 mg, 0.04 mmol) and a solution of isopropylcarbonochloridate (5 mg, 0.04 mmol) in THF (1 mL) dropwise at 0° C. Thereaction was stirred at 0° C. for 20 mins. After that, a solution ofNH₄OH (2 mg, 0.04 mmol) was added to the mixture at 0° C., and themixture was stirred another 5 mins at 0° C., quenched with H₂O (5 mL),and the organic solution was concentrated. To the residue was added EA(10 mL), which was then washed with H₂O (3×10 mL). The organic layer wasdried over Na₂SO₄ and concentrated. The residue was purified on a silicagel column by eluting with EA to obtain 5 mg (50% yield) of Compound Vas a white solid. MS (ESI): [M+H]⁺=486.9. ¹H NMR (400 MHz, DMSO-d6) δ9.22 (s, 1H), 8.96 (s, 3H), 8.66 (s, 1H), 8.52 (s, 1H), 8.44 (s, 1H),8.10 (s, 1H), 8.00 (s, 1H), 7.93 (s, 1 H).

Example 6 (Z)-3-(3-(3-(Pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(thiazol-2-yl)acrylohydrazide(VI)

Step 1: Synthesis of(Z)-3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(thiazol-2-yl)acrylohydrazide(VI)

To a solution of compound 15 (100 mg, 0.24 mmol), 2-hydrazineylthiazolehydrochloride (34) (45 mg, 0.29 mmol) in CH₃CN:EA (4 mL:2 mL) was addedDIEA (62 mg, 0.48 mmol) and T313 (228 mg, 0.36 mmol, 50% in EA) at 0° C.and then the mixture was stirred at 0° C. for 10 h. The mixture wasconcentrated. To the residue was added EA (50 mL) and the residue waswashed with H₂O (3×50 mL). The organic solution was concentrated andpurified by prep-TLC(EA) to obtain 8 mg (7% yield) of Compound VI as agray solid. MS (ESI): [M+H]⁺=506.9. ¹H NMR (400 MHz, DMSO-d6) δ 10.92(s, 1 H), 9.58 (s, 1H), 8.65 (s, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 7.57(d, J=12 Hz, 1H), 7.22 (d, J=4 Hz, 1 H), 6.89 (d, J=4 Hz, 1H), 6.04 (d,J=8 Hz, 1H).

Example 7(Z)—N′-(3-(3-(3-(Pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)cyclopropanecarbohydrazide(VII)

Step 1: Synthesis of(Z)—N-(3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)cyclopropanecarbohydrazide(VII)

To a solution of compound 15 (50 mg, 0.12 mmol),cyclopropanecarbohydrazide (18 mg, 0.18 mmol) in DCM:EA (3 mL:3 mL) wasadded DIEA (62 mg, 0.48 mmol) and T3P (305 mg, 0.48 mmol, 50% in EA) at0° C. then the mixture was stirred at 0° C. for 1 h. The mixture wasconcentrated. To the residue was added EA (50 mL), which was washed withH₂O (3×50 mL). The organic solution was concentrated and purified byprep-TLC (EA) to obtain 40 mg (68% yield) of Compound VII as a whitesolid. MS (ESI): [M+H]⁺=492.8. ¹H NMR (400 MHz, DMSO-d6) δ 10.54 (s,1H), 10.31 (s, 1H), 9.63 (s, 1H), 8.67 (s, 1H), 8.56 (s, 1H), 8.42 (s,1H), 7.49 (d, J=12 Hz, 1H), 6.02 (d, J=12 Hz, 1H), 1.71-1.67 (m, 1H),0.79-0.74 (m, 4H).

Example 8 (Z)—N′-Isobutyryl-3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide(VIII)

Step 1:(Z)—N-Isobutyryl-3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide(VIII)

To a solution of compound 15 (50 mg, 0.12 mmol) and isobutyrohydrazide(18 mg, 0.18 mmol) in DCM:EA (3 mL:3 mL) was added DIEA (62 mg, 0.48mmol) and T3P (305 mg, 0.48 mmol, 50% in EA) at 0° C. and then themixture was stirred at 0° C. for 1 h. The mixture was concentrated. Tothe residue was added EA (50 mL), which was washed with H₂O (3×50 mL).The organic solution was concentrated and purified by prep-TLC(EA) toobtain 40 mg (68% yield) of Compound VIII as a white solid. MS (ESI):[M+H]⁺=494.8. ¹H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 10.02 (s, 1H),9.64 (s, 1H), 8.67 (s, 1H), 8.56 (s, 1H), 8.42 (s, 1H), 7.59 (d, J=12Hz, 1H), 6.02 (d, J=12 Hz, 1H), 2.55-2.48 (m, 1H), 1.06 (d, J=8 Hz, 6H).

Example 9(Z)—N′-(3-(3-(3-(Pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)butyrohydrazide(IX)

Step 1:(Z)—N′-(3-(3-(3-(Pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)butyrohydrazide(IX)

To a solution of compound 15 (50 mg, 0.12 mmol) and butyrohydrazide (18mg, 0.18 mmol) in DCM:EA (3 mL:3 mL) was added DIEA (62 mg, 0.48 mmol)and T3P (305 mg, 0.48 mmol, 50% in EA) at 0° C. and then the mixture wasstirred at 0° C. for 1 h. The mixture was concentrated. To the residuewas added EA (50 mL), which was washed with H₂O (3×50 mL). The organicsolution was concentrated and purified by prep-TLC(EA) to obtain 40 mg(68% yield) of Compound IX as a white solid. MS (ESI): [M+H]⁺=494.8. ¹HNMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 10.04 (s, 1H), 9.63 (s, 1H),8.67 (s, 1H), 8.55 (s, 1H), 8.42 (s, 1H), 7.49 (d, J=12 Hz, 1H), 6.03(d, J=12 Hz, 1H), 2.16 (t, J=8 Hz, 2H), 1.61-1.52 (m, 2H), 0.90 (t, J=8Hz, 3H).

Example 10(Z)—N′-(3-(3-(3-(Pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)cyclobutanecarbohydrazide(X)

Step 1: Synthesis of tert-butyl2-(cyclobutanecarbonyl)hydrazine-1-carboxylate (43)

To a solution of compound 41 (500 mg, 5 mmol) and compound 42 (726 mg,5.5 mmol) in DCM (20 mL) was added DIEA (1.29 g, 10 mmol) and T3P (6.36g, 10 mmol, 50% in EA) at 0° C. and the mixture was stirred at 25° C.for 1 h. The mixture was washed with H₂O (3×20 mL). The organic solutionwas concentrated and dried in vacuo to obtain 1 g (93% yield) ofcompound 43 as a white solid. MS (ESI):[M+H]⁺=215.4.

Step 2: Synthesis of Cyclobutanecarbohydrazide Hydrochloride (44)

To a solution of compound 43 (1 g, 4.7 mmol) in DCM (20 mL) was added anHCl solution in dioxane (10 mL, 4M) and the mixture was stirred at 25°C. for 30 mins. The mixture was concentrated and dried in vacuo toobtain 0.7 g (99% yield) of compound 44 as a white solid. MS (ESI):[M+H]⁺=115.3.

Step 3: Synthesis of(Z)—N′-(3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)cyclobutanecarbohydrazide(X)

To a solution of compound 15 (50 mg, 0.12 mmol) and compound 44 (28 mg,0.18 mmol) in DCM:EA (3 mL:3 mL) was added DIEA (62 mg, 0.48 mmol) andT3P (305 mg, 0.48 mmol, 50% in EA) at 0° C. and then the mixture wasstirred at 0° C. for 1 h. The mixture was concentrated. To the residuewas added EA (50 mL), which was washed with H₂O (3×50 mL). The organicsolution was concentrated and purified by prep-TLC (EA) to obtain 11 mg(18% yield) of Compound X as a white solid. MS (ESI): [M+H]⁺=506.9. ¹HNMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 9.93 (s, 1H), 9.64 (s, 1H), 8.67(s, 1H), 8.56 (s, 1H), 8.42 (s, 1H), 7.49 (d, J=12 Hz, 1H), 6.02 (d,J=12 Hz, 1H), 3.18-3.10 (m, 1H), 2.23-1.90 (m, 6H).

Example 11(Z)-1-Methyl-N′-(3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)cyclopropane-1-carbohydrazide(XI)

Step 1: (Z)-1-Methyl-N′-(3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)cyclopropane-1-carbohydrazide(XI)

To a solution of compound 15 (40 mg, 0.1 mmol) and compound 44 (17 mg,0.15 mmol) in DCM:EA (3 mL:3 mL) was added DIEA (52 mg, 0.4 mmol) andT3P (254 mg, 0.4 mmol, 50% in EA) at 0° C. and then the mixture wasstirred at 0° C. for 1 h. The mixture was concentrated. To the residuewas added EA (50 mL), which was washed with H₂O (3×50 mL). The organicsolution was concentrated and purified by prep-TLC (EA) to obtain 21 mg(41% yield) of Compound XI as a white solid. MS (ESI): [M++H]⁺=506.9. ¹HNMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.65 (s, 1H), 9.62 (s, 1H), 8.65(s, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 7.49 (d, J=8 Hz, 1H), 6.02 (d, J=8Hz, 1H), 1.31 (s, 3H), 1.02 (s, 2H), 0.62 (s, 2H).

Example 12(Z)—N′-(3-Chloro-2-(hydroxymethyl)-2-methylpropanoyl)-3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide(XII)

Step 1: Synthesis of tert-butyl2-(3-methyloxetane-3-carbonyl)hydrazine-1-carboxylate (47)

To a solution of compound 46 (116 mg, 1 mmol) and compound 42 (145 mg,1.1 mmol) in DCM (10 mL) was added DIEA (258 mg, 2 mmol) and T3P (1.27g, 2 mmol, 50% in EA) at 0° C. and then the mixture was stirred at 25°C. for 1 h. The mixture was washed with H₂O (3×15 mL). The organicsolution was concentrated and dried in vacuo to obtain 230 mg (99%yield) of compound 47 as a white solid. MS (ESI): [M+H]⁺=231.4.

Step 2: Synthesis of 3-chloro-2-(hydroxymethyl)-2-methylpropanehydrazidehydrochloride (48)

To a solution of compound 47 (230 mg, 1 mmol) in DCM (10 mL) was addedthe HCl solution in dioxane (10 mL, 4M) and then the mixture was stirredat 25° C. for 30 mins. The mixture was concentrated and dried in vacuoto obtain 200 mg (99% yield) of compound 48 as a white solid. MS (ESI):[M+H]⁺=166.3.

Step 3: Synthesis of(Z)—N′-(3-chloro-2-(hydroxymethyl)-2-methylpropanoyl)-3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide(XII)

To a solution of compound 15 (59 mg, 0.14 mmol) and compound 48 (45 mg,0.22 mmol) in DCM:EA (3 mL:3 mL) was added DIEA (72 mg, 0.56 mmol) andT3P (356 mg, 0.56 mmol, 50% in EA) at 0° C. and then the mixture wasstirred at 0° C. for 1 h. The mixture was concentrated. To the residuewas added EA (50 mL), which was washed with H₂O (3×50 mL). The organicsolution was concentrated and purified by prep-TLC(EA) to obtain 10 mg(13% yield) of Compound XII as a white solid. MS (ESI): [M+H]⁺=559.0. ¹HNMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.88 (s, 1H), 9.63 (s, 1H), 8.66(s, 1H), 8.55 (s, 1H), 8.40 (s, 1H), 7.49 (d, J=12 Hz, 1H), 6.03 (d,J=12 Hz, 1H), 5.16 (s, 1H), 3.81 (s, 2H), 3.59 (s, 2H), 1.22 (s, 3H).

Example 13 General synthesis of(Z)-3-methyl-N′-(3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)butanehydrazide(XIII)

Step 1: Synthesis of(Z)-3-methyl-N′-(3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)butanehydrazide(XIII)

To a solution of compound 15 (50 mg, 0.12 mmol) and3-methylbutanehydrazide (21 mg, 0.18 mmol) in DCM:EA (3 mL:3 mL) wasadded DIEA (62 mg, 0.48 mmol) and T3P (305 mg, 0.48 mmol, 50% in EA) at0° C. and then the mixture was stirred at 0° C. for 1 h. The mixture wasconcentrated. To the residue was added EA (50 mL), which was washed withH₂O (3×50 mL). The organic solution was concentrated and purified byprep-TLC(EA) to obtain 37 mg (61% yield) of Compound XIII as a whitesolid. MS (ESI): [M+H]⁺=508.9. ¹H NMR (400 MHz, DMSO-d6) δ 10.50 (s,1H), 10.02 (s, 1H), 9.63 (s, 1H), 8.67 (s, 1H), 8.55 (s, 1H), 8.42 (s,1H), 7.49 (d, J=12 Hz, 1H), 6.03 (d, J=12 Hz, 1H), 2.07-1.95 (m, 3H),0.93 (d, J=8 Hz, 6H).

Example 14 General synthesis of(Z)—N-acetyl-3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide(XIV)

Step 1: Synthesis of acetohydrazide (52)

To a solution of compound 51 (2.4 g, 27.3 mmol) in EtOH (5 mL) was addedhydrazine hydrate (1.03 g, 20.6 mmol) and then the mixture was stirredat 80° C. for 12 h. The mixture was concentrated and dried over vacuo toobtain 1.3 g (86% yield) of compound 52 as a white solid.

Step 2: Synthesis of(Z)—N′-acetyl-3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide(XIV)

To a solution of compound 15 (50 mg, 0.12 mmol) and compound 52 (14 mg,0.18 mmol) in DCM:EA (3 mL:3 mL) was added DIEA (62 mg, 0.48 mmol) andT3P (305 mg, 0.48 mmol, 50% in EA) at 0° C. and then the mixture wasstirred at 0° C. for 1 h. The mixture was concentrated. To the residuewas added EA (50 mL), which was washed with H₂O (3×50 mL). The organicsolution was concentrated and purified by prep-TLC(EA) to obtain 20 mg(36% yield) of Compound XIV as a white solid. MS (ESI): [M+H]⁺=466.8. ¹HNMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 10.09 (s, 1H), 9.62 (s, 1H),8.66 (s, 1H), 8.55 (s, 1H), 8.42 (s, 1H), 7.49 (d, J=12 Hz, 1H), 6.03(d, J=12 Hz, 1H), 1.91 (s, 3H).

Example 15(Z)-3-(3-(3-(Pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-propionylacrylohydrazide(XV)

Step 1: Synthesis of tert-butyl 2-propionylhydrazine-1-carboxylate (57)

To a solution of compound 56 (74 mg, 1 mmol) and compound 42 (145 mg,1.1 mmol) in DCM (10 mL) was added DIEA (258 mg, 2 mmol) and T3P (1.27g, 2 mmol, 50% in EA) at 25° C. and then the mixture was stirred at 25°C. for 1 h. The mixture was washed with H₂O (3×20 mL). The organicsolution was concentrated and dried in vacuo to obtain 190 mg (99%yield) of compound 57 as a white solid. MS (ESI): [M+H]⁺=192.3.

Step 2: Synthesis of propionohydrazide hydrochloride (58)

To a solution of compound 57 (190 mg, 1 mmol) in DCM (10 mL) was addedan HCl solution in dioxane (10 mL, 4M) and then the mixture was stirredat 25° C. for 30 mins. The mixture was concentrated and dried over vacuoto obtain 120 mg (94% yield) of compound 58 as a white solid.

Step 3: Synthesis of(Z)-3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-propionylacrylohydrazide(XV).

To a solution of compound 15 (50 mg, 0.12 mmol) and compound 58 (23 mg,0.18 mmol) in DCM:EA (3 mL:3 mL) was added DIEA (62 mg, 0.48 mmol) andT3P (305 mg, 0.48 mmol, 50% in EA) at 0° C. and then the mixture wasstirred at 0° C. for 1 h. The mixture was concentrated. To the residuewas added EA (50 mL), which was washed with H₂O (3×50 mL). The organicsolution was concentrated and purified by prep-TLC(EA) to obtain 24 mg(42% yield) of Compound XV as a white solid. MS (ESI): [M+H]⁺=480.9. ¹HNMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 10.03 (s, 1H), 9.63 (s, 1H),8.67 (s, 1H), 8.56 (s, 1H), 8.42 (s, 1H), 7.49 (d, J=12 Hz, 1H), 6.03(d, J=12 Hz, 1H), 2.20 (q, J=8 Hz, 2H), 1.05 (t, J=8 Hz, 3H).

Example 16(Z)—N′-(3-(3-(3-(Pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)cyclopentanecarbohydrazide(XVI)

Step 1: Synthesis of tert-butyl2-(cyclopentanecarbonyl)hydrazine-1-carboxylate (62)

To a solution of compound 61 (114 mg, 1 mmol) and compound 42 (145 mg,1.1 mmol) in DCM (10 mL) was added DIEA (258 mg, 2 mmol) and T3P (1.27g, 2 mmol, 50% in EA) at 25° C. and then the mixture was stirred at 25°C. for 1 h. The mixture was washed with H₂O (3×20 mL). The organicsolution was concentrated and dried in vacuo to obtain 220 mg (96%yield) of compound 62 as a white solid. MS (ESI): [M+H]⁺=229.3.

Step 2: Synthesis of cyclopentanecarbohydrazide hydrochloride (63)

To a solution of compound 62 (220 mg, 1 mmol) in DCM (10 mL) was addedan HCl solution in dioxane (10 mL, 4M) and then the mixture was stirredat 25° C. for 30 mins. The mixture was concentrated and dried in vacuoto obtain 160 mg (97% yield) of compound 63 as a white solid. MS (ESI):[M+H]⁺=129.3.

Step 3: Synthesis of (Z)—N′-(3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)cyclopentanecarbohydrazide (XVI)

To a solution of compound 15 (50 mg, 0.12 mmol), and compound 63 (30 mg,0.18 mmol) in DCM:EA (3 mL:3 mL) was added DIEA (62 mg, 0.48 mmol) andT3P (305 mg, 0.48 mmol, 50% in EA) at 0° C. and then the mixture wasstirred at 0° C. for 1 h. The mixture was concentrated. To the residuewas added EA (50 mL), which was washed with H₂O (3×50 mL). The organicsolution was concentrated and purified by prep-TLC(EA) to obtain 30 mg(48% yield) of Compound XVI as a white solid. MS (ESI): [M+H]⁺=520.9. ¹HNMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 10.02 (s, 1H), 9.65 (s, 1H),8.67 (s, 1H), 8.56 (s, 1H), 8.42 (s, 1H), 7.49 (d, J=12 Hz, 1H), 6.02(d, J=12 Hz, 1H), 2.72-2.65 (m, 1H), 1.84-1.52 (m, 8H).

Example 17(Z)—N′-(2-Methyl-2-(methyl-d3)propanoyl-3,3,3-d₃)-3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide(XVII)

Step 1: Synthesis of 2-methylpropanoic-3,3,3-d₃ acid (66)

To a solution of LDA (50 mL, 74.3 mmol) in THF (150 mL) was addedcompound 65 (2.2 g, 29.7 mmol) at 0° C. under a nitrogen atmosphere andthen the mixture was stirred at 80° C. for 2 h, cooled to 0° C., andthen CD3I (4.8 g, 32.7 mmol) was added dropwise and stirred at 80° C.for 10 h. To the mixture was added H₂O (50 mL), which was extracted withEA (50 mL). The inorganic layer was acidified with IN HCl to pH=4 andthen extracted with EA (50 mL). The organic solution was dried overNa₂SO₄, filtered, and concentrated to obtain 1.68 g (62% yield) ofcompound 66 as a light-yellow oil. 1H NMR (400 MHz, CDCl₃) δ 2.57 (q,J=8 Hz, 1H), 1.19 (d, J=8 Hz, 3H).

Step 2: Synthesis of 2-methyl-2-(methyl-d3)propanoic-3,3,3-d₃ acid (67)

To a solution of LDA (31 mL, 46.3 mmol) in THF (90 mL) was addedcompound 66 (1.68 g, 18.5 mmol) at 0° C. under a nitrogen atmosphere andthen the mixture was stirred at 80° C. for 2 h, cooled to 0° C., andthen CD3I (3 g, 20.8 mmol) was added dropwise and stirred at 80° C. for10 h. To the mixture was added H₂O₂O (50 mL) then extracted with EA (50mL). The inorganic layer was acidified with 1N HCl to pH=4 and thenextracted with EA (50 mL). The organic solution was dried over Na₂SO₄,filtered, and concentrated to obtain 1.17 g (59% yield) of compound 67as a yellow oil. 1H NMR (400 MHz, CDCl₃) δ 1.22 (s, 3H).

Step 3: Synthesis of tert-butyl2-(2-methyl-2-(methyl-d₃)propanoyl-3,3,3-d₃)hydrazine-1-carboxylate (68)

To a solution of compound 67 (540 mg, 5 mmol), tert-butylhydrazinecarboxylate (660 mg, 5 mmol), and Et₃N (1.01 g, 10 mmol) in DCM(50 mL) was added EDCl (1.05 g, 5.5 mmol) and HOBT (740 mg, 5.5 mmol) at25° C. and then the mixture was stirred at 25° C. for 12 h. Then themixture was washed with H₂O (3×50 mL). The organic solution wasconcentrated and purified on silica gel column by eluting with PE:EA(5:1 to 3:1) to obtain 412 mg (37% yield) of compound 68 as a whitesolid. MS (ESI): [M+H]⁺=223.5. ¹H NMR (400 MHz, CDCl₃) δ 7.37 (s, 1H),6.48 (s, 1H), 1.47 (s, 9H), 1.24 (s, 3H).

Step 4: Synthesis of 2-methyl-2-(methyl-d3)propanehydrazide-3,3,3-d₃hydrochloride (69)

To a single-neck flask was added compound 68 (412 mg, 1.9 mmol) and HClsolution in dioxane (10 mL, 4M). The mixture was stirred at 25° C. for 1h. The mixture was concentrated and dried in vacuo to obtain 300 mg (99%yield) of compound 69 as a white solid. MS (ESI): [M+H]⁺=123.3.

Step 5: Synthesis of(Z)—N′-(2-methyl-2-(methyl-d3)propanoyl-3,3,3-d₃)-3-(3-(3-(pentafluorosulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide(XVII)

To a solution of compound 15 (700 mg, 1.7 mmol) and compound 69 (300 mg,1.88 mmol) in DCM (50 mL) was added DIEA (877 mg, 6.8 mmol) and T3P (4.3g, 6.8 mmol, 50% in EA) at −78° C., the mixture was stirred at −78° C.for 30 mins, and then warmed to 0° C. and stirred for 1 h. The mixturewas concentrated at 35° C. in vacuo. To the residue was added EA (100mL) and washed with H₂O (3×100 mL) and brine (3×100 mL). The organicsolution was dried over Na₂SO₄, filtered and concentrated to obtain acrude product which was triturated with CH₃CN (15 mL) for 12 h,filtered. The filter cake was collected and triturated with DCM (15 mL)for 12 h and then filtered. The filter cake was washed with DCM (15 mL),collected and dried in vacuo for 5 h to obtain 670 mg (77% yield) ofCompound XVII as a white solid. MS (ESI): [M+H]⁺=514.9. ¹H NMR (400 MHz,DMSO-d6) δ 10.36 (s, 1H), 9.67 (s, 1H), 9.64 (s, 1H), 8.67 (s, 1H), 8.56(s, 1H), 8.44 (s, 1H), 7.49 (d, J=12 Hz, 1H), 6.02 (d, J=12 Hz, 1H),1.16 (s, 3H).

Example 18 Synthesis of (Z)-3-(3-(3,5-bi s(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(pyrimidin-5-yl)acrylamide(XXIV)

Compound XXIV was synthesized adapting the procedure described inExample 4 except that compound 14 was replaced with the —CF₃ analog,isopropyl(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylate.

Example 19 Inhibition of Cell Proliferation Assay

CellTiter-Glo® Luminescent Cell Viability assay (with Promega CellTiter96® Luminescent CellTiter-Glo® kit) was used to study the proliferationinhibition by test compounds. Compounds were resuspended in DMSO to makea 25 mM stock suspension. Cells of cancer cell lines or normal tissueswere seeded in 96-well plates at 1,500 to 5,000 cells/well overnight.Compounds were 2- or 3-fold diluted serially to obtain 10concentrations. Then, the drugs were added to the cell wells by Bravo(Agilent) and incubated for 72 hours. The cells were lysed by addingCellTiter-Glo® Reagent (per manufacturer's instructions) andsubsequently, the luminescence was read using EnVision® (PerkinElmer).

The percent of growth was calculated as follows. DMSO-treated cells wereemployed as vehicle control (High control, HC) and culture medium alonewas employed as background (Low control, LC). % growth=100×(Lumsample−Lum LC)/(Lum HC−Lum LC). The IC₅₀ was calculated byconcentration−response curve fitting using Graphpad Prism.

Hematological cancer cell lines tested included OCI-AML3, MV-4-11, KG-1,Kasumi-1, K562, THP-1; solid cancer cell lines tested included U87MG,U251, T98G, LN229, A172, H460, H2009, A549; normal cell lines testedincluded HCN2 and 3T3-L1. The results were shown in Table 1, where thetest compounds showed growth inhibition on cancer cell lines of brain,lung, and blood. However, they were not toxic to in vitro culturednormal cells.

TABLE 1 Growth inhibition by test compounds in cancer and normal celllines (IC50, nM). Cell lines Compound I Compound II Compound IIICompound IV U87MG 591.5 630 1743.8 194 T98G NA 1916 6253 NA LN-229 NA805 1796 NA U251 NA 2338 3770 NA A549 1489 NA NA 1865 H460 294 NA NA 306H2009 521 NA NA 453 MV411 NA NA NA 110 KG1 NA NA NA 698 Kasumi-1 NA NANA 124 OCI-AML3 NA NA NA 341 K562 NA NA NA 1748 THP-1 NA NA NA 838 HCN225813.75 44748.65 >50000 NA 3T3-L1 >50000 NA NA NA NA. Not available.

Example 20 REV-GFP Translocation Assay

Previous studies suggested that the nuclear accumulation of REV cargo isa marker of CRM1 inhibition. SINE (Selective Inhibitor of NuclearExport) treatment induced a clear and rapid shift of REV from acytoplasmic localization to the nucleus in a dose dependent manner. Toevaluate XPO1 inhibition by test compounds, REV-GFP U2OS clones weregenerated by HD Biosciences Co. LTD in China, and cells were culturedwith growth medium. Then cells were seeded into 96 well plates at 7,000cells/well in 100 μL growth medium in 37° C., 5% CO2 incubatorovernight. The highest Leptomycin B (LMB) concentration was set to 50 nMand serially diluted as the positive control, while the highestconcentrations of other compounds were set to 10 μM. The cells treatedwith various drugs or DMSO, were incubated at 37° C. and 5% CO₂ for 1 h.Then, cells were fixed with 4% formaldehyde for 15 min at roomtemperature.

The cells were washed and stained with 100 μL Hoechst 33342 workingsolution for 10 min at room temperature in dark, after which the cellfluorescence was imaged with the High-Content Imaging System,ImageXpress® (Molecular Devices) using the 20× objective. The filterswere set for Hoechst (350/461 nm) and GFP/FITC (488/509 nm) (wavelengthfor excitation and emission maxima). The % effect of REV nucleartranslocation was calculated with the following formula: %effect=(I_(TEST)−I_(CTRL))/(I_(LMB)−I_(CTRL))×100I_(TEST)—signals fromtesting compounds; I_(LMB)—signals of 50 nM LMB group; I_(CTRL)—signalsof vehicle control group.

After treated with LMB and Compound III respectively for 1 h, there wasdose-dependent for the nuclear redistribution of REV and there was nodecrease in cell viability by Compound III at all concentrations tested.The data shows Compound III increases REV nuclear accumulation byinhibiting CRM1 with no effect on cell viability. The results are shownin FIGS. 1A-1C and 2A-2B. FIGS. 1A-1C show the effects of LMB on Revredistribution in Rev-GFP-U2OS Cells. (1A. Representative images of doseresponse effects of LMB for 1 h, Green indicated Rev conjugated EGFP;1B. Dose response curves in the Rev redistribution with LMB treatment.The Vehicle group was set to zero and the 50 nM LMB group was used torepresent 100% effect. Values denoted mean±SEM (n=2). EC50=0.11 nM; 1C.Effect of LMB on cell number. The analyzed relative ratios of each groupwere normalized to Vehicle group. All values denoted are mean±SEM(n=2)). FIGS. 2A-2B show EC50 in REV cargo inhibition by Compound III,and it did not affect cell viability. Rev-GFP was used to evaluate othertest compounds, as shown in Table 2.

TABLE 2 Quantitation of inhibition of XPO1 cargo REV nuclear export bytest compounds in REV-EGFP U2OS cells. Compound Rev-GFP/EC50 (nM)Compound I 12.0 Compound II 28.5 Compound III 211.4 Compound IV 14.8Compound VI 25.2

Example 21 Compound Washout Assay

A compound washout assay was performed to demonstrate sustained, butreversible XPO1 inhibition.

In order to evaluate the duration of XPO1 inhibition by test compoundson XPO1 protein after washout, washout assay was performed using REV-GFPcells. The test compounds and positive control were added to the cellwell, and the plate was incubated the at 37° C. and 5% CO₂ for 1 h. Thedrug-containing media were removed, the cells were washed, and the freshmedia were added. The cells were imagined at the specified time points0, 4, 24, 48, 72, and 96 hours to evaluate the inhibition of REV nuclearexport. With 50 nM LMB, there was sustained retention of REV protein inthe nucleus, up to 24 hours post washout, and the effect graduallydecreased to 30% at 72 hours. However, LMB showed toxicity, as indicatedby the decrease in cell number, compared to the control. Compound III atEC90 also inhibited nuclear export of REV. Starting at 4 hours postwashout, the effect gradually diminished and lost at 24 hours. The cellswere well tolerated with Compound III treatment and no decrease in thecell number was observed. In conclusion, compared to positive controlLMB Compound III which also covalently bound to the XPO1 protein, showedsignificant and reversible effect on increasing Rev redistribution innucleus without any side effect on cell growth in 24 h. The results areshown in FIGS. 3A-3C and 4A-4C. FIGS. 3A-3C show sustained XPO1inhibition by LMB in washout study (3A. Representative images of LMBeffect on Rev redistribution post washout. 3B. Summary of LMB effect onthe Rev redistribution post washout. 3C. Effect of LMB on cellviability. The analyzed relative ratios of each group were normalized toeach group at 0 h. All values denoted were mean±SEM (n=3).). FIGS. 4A-4Cshow Compound III's washout effects on Rev redistribution inRev-EGFP-U2OS Cells. Compound III at EC90 and EC50 (400 nM and 120 nM)were evaluated in this washout REV-EGFP translocation study. CompoundIII at EC50 showed about 40% effect on nuclear retention of REV,following 1-hour treatment. This effect was gradually diminished to 20%at 4 hours post washout and completely lost at 24 hours. Whereas at 400nM, Compound III showed sustained XPO1 inhibition at 4 hours andgradually diminished by 24 hours. No Significant effect on cellviability was observed. In conclusion, Compound III showed a time- anddose-dependent inhibition of XPO1 protein, and the effect was sustainedfor 4 hours and reversible. 4A. Representative images of Compound IIIeffect on Rev redistribution post washout. 4B. Summary of Compound IIIeffect on the Rev redistribution post washout. 4C. Effect of CompoundIII on cell viability.

Example 22 Pharmacokinetic (PK) Profile and Ratio of Brain to Plasma AUC

Blood was collected from mice (n=3, or 5) to contribute to the total of10 time points (pre-dose, 5 min, 15 min, 30 min, 1 hour, 2 hours, 4hours, 8 hours, 12 hours and 24 hours). At the designated time points,animals were anaesthetized under isoflurane, and approximately 110 μL ofblood per time point was collected via retro-orbital puncture intopre-cooled K2EDTA tubes. Blood samples were put on wet ice andcentrifuged (2000 g, 5 min at 4° C.) to obtain plasma within 30 minutesof sample collection. All samples were stored frozen at approximately−80° C. until analysis. Prior to analysis, samples were mixed withinternal standard in acetonitrile, vortexed, centrifuged, andsupernatant was injected for analysis. Concentration of compounds inplasma was determined using LC-MS-MS instrumentation (API 4000, TripleQuadrupole LC/MS/MS Mass Spectrometer). AUC values were calculated usingPhoenix Win Nonlin 6.3 software package, PO-Noncompartmental model 200(extravascular input). The results are shown in Table 3.

TABLE 3 PK parameters of represented compounds. T_(1/2) C₀ AUC_(0-last)Vdss Cl MRT_(0-last) I.V. (h) (ng/mL) (ng · h/mL) (L/kg) (mL/min/kg) (h)Compound I  1.62 1009 1039 1.68 16.0 1.56 Compound II 3.82 558 1623 3.2010.0 4.76 T_(1/2) T_(max) C_(max) AUG_(0-inf) MRT_(0-last) MRT_(0-inf)P.O. (h) (h) (ng/mL) (ng · h/mL) (h) (h) Compound I  4.72 0.75 255310430 4.51 5.55 Compound II 4.72 2.0 1596 13905 6.90 7.84

Ratio of Brain to Plasma (B:P).

A separate group of mice or rat (n=3, or 5) were dosed (PO at 10 mg/kg)and then sacrificed at the time of maximal plasma concentration (Tmax at1-hour post-dose), at which time terminal plasma and brain tissue werecollected. Following collection, brain tissue was rinsed with coldsaline, dried on filter paper, weighed and snap-frozen by placing on dryice. All samples were stored frozen at approximately −80° C. untilanalysis. At the time of analysis, brain tissue was homogenized(homogenizing solution PBS, pH 7.4), mixed with internal standard inacetonitrile, vortexed, centrifuged, and supernatant was injected foranalysis. Concentration of compounds in plasma was determined usingLC-MS-MS instrumentation (API 4000, Triple Quadrupole LC/MS/MS MassSpectrometer). Plasma samples were treated with the identical method(except homogenization step) and the concentration of compound in eachmatrix was calculated based on generated standard curves. The result ofthe PK assay and the B:P ratio determination are shown in Table 4 andFIG. 5 . FIG. 5 shows the comparison of THE brain behavior of CompoundIII with KPT350 in cassette PK of brain penetration

TABLE 4 The ratio of plasma to brain in rats at the dose of 10 mg/kg viaPO administration. Compound I Compound II Brain/Plasma Brain/PlasmaTime/h Ratio (ng/g) Ratio (ng/g) 0.25 0.386 0.716  810:319  419:301 10.707 0.954 1887:1301 1274:1191 8 0.782 1.40  252:194  677:937

Example 23 Maximum Tolerance Dose (MTD) Study

Female BALB/c Nude mice (Supplied by Beijing AniKeeper Biotech Co.,Ltd., 6-8 weeks old/18-22 g) were quarantined for 7 days before thestudy. The general health of the animals was evaluated by aveterinarian. Animals with abnormalities were excluded prior the study.General procedures for animal care and use were in accordance with thestandard operating procedures (SOPs) of Pharmaron, Inc. The animals weredosed as summarized in table 5.

TABLE 5 Group and treatments. Animals/ Dose Vol Group Drug group (mg/kg)(ml/kg) Route Regimen 1 Compound I 5 25 10 p.o. qod × 3 (two weeks) 2KPT-330 5 25 10 p.o. qod × 3 (two weeks)

Body weights of all animals was measured daily. General behavior such asmobility, food and water consumption (by cage side checking only),eye/hair matting and any other abnormal effect were routinely monitored.Any mortality and/or abnormal clinical signs were recorded. Animalsshowing obvious signs of severe distress and/or pain were humanelysacrificed by carbon dioxide followed by cervical dislocation to ensuredeath. Animals were euthanized in case of following situations, obviousbody weight loss>20% or animals could not get to adequate food or water.The results are shown in FIG. 6 . FIG. 6 shows the percent of bodyweight change % of mice in MTh study. In the KPT-330 group, afterone-week dosing, all mice were dead, or anaesthetized for the weightlost up to 20%; however, all mice in the Compound I group (25 mg/kg PO,3 times a week on every other day for 2 weeks) survived. administrationformulation: 10% NMP/10% Solutl/80% (0.5% Poloxamer 188+0.5% PVP).

Example 24 Evaluation of the Antitumor Effect of Compound III onU87MG-Luc Human Glioblastoma Orthotopic Model in BALB/c Nude Mice

23.1. Study Design.

Animals: Female BALB/c Nude mice (Supplied by Beijing AniKeeper BiotechCo., Ltd., 6-8 weeks old/18-22 g) were used. General procedures foranimal care and using were in accordance with the standard operatingprocedures (SOPs) of Pharmaron, Inc.

Grouping and Treatments: Grouping and treatment were started on Day 7post tumor cells inoculation. Mice were imaged to monitor the tumorgrowth, then mice were randomly assigned to respective groups using acomputer-generated randomization procedure. All test articles wereadministered orally 20 mg/kg with 3 times/week, for 4 weeks post tumorimplantations (n=12 per group).

23.2. Experimental Method and Measurement Parameters.

Cell Culture: The Human glioblastoma U87-luc tumor cell line wasmaintained in vitro as monolayer culture and used for tumor inoculation

Tumor Inoculation and Randomization: 2.5×10⁵ luciferase-expressingU87MG-luc tumor cells suspended in 2 μL MEM medium were injected intothe right forebrain by positioning the needle at AP: 2.0 mm, ML: 0.5-1.0mm, DV: 3.0 mm from bregma. The injection was slowly proceeding over aone-minute period. Upon completing injection, the needle was retainedfor another minute. Measurement Parameters: Tumor growth (monitored byimage analysis), body weight and survival days were recorded.

Termination Criterion: Individual animal was humanely sacrificed bycarbon dioxide when body weight loss >20% and animals could not get toadequate food or water.

Statistical Analysis: Data was recorded as means±standard error of themean for all measurement parameters as study designed. All statisticaltests were conducted by SPSS 17.0 statistical software, and the level ofsignificance is set at p<0.05.

23.3. Results.

Overall, Compound III at 20 mg/kg exhibited pronounced antitumoractivity with 99% reduction in bioluminescence signal compared with thevehicle control group (p values<0.05) at the end of the treatmentperiod. The medium survival time (MST) of animals in vehicle group was39.5 days, as compared to 47 days in compound III-treated group with a pvalue<0.0007.

Regarding the safety profile, Compound III at 20 mg/kg was welltolerated by most animals, although individual animal had bodyweightloss less than 10%, which required skipped doses. No other grossclinical abnormalities were observed during the treatment period. Inconclusion, Compound III, given orally at 20 mg/kg, 3 times per week,for 4 weeks, was able to significantly prolong the survival of GBMtumor-bearing mice. Taken together, compound III demonstratedBBB-penetrating ability by inhibiting GBM tumor growth and prolongingthe survival of animals in the group with U87MG-luc orthotopic tumor.

The results are shown in FIGS. 7 ˜9. FIG. 7 shows tumor growthinhibition by compound III in U87MG-Luc orthotopic model (logarithmicscale on Y-axis, * p<0.05). FIG. 8 shows the survival curve of vehiclevs compound III-treated group following 4 weeks of treatment at 20mg/kg, tiw. FIG. 9 shows body weight changes during and followingtreatment (Day 7-Day 65).

Example 25 Evaluation of PD Effects of Compound III in U87MG-LucOrthotopic Mouse Model by IHC

Based on the bioluminescent signal of tumor, mice were randomly assignedto respective groups using a computer-generated randomization procedure,which included vehicle and compound III-treated groups, respectively,with 5 animals per group. Compound III (20 mg/kg) was given orally 3times a week (on Day 1, 3, 5) for 2 weeks. Animals for IHC study wereeuthanized at 6 hours after the last dose and perfused with normalsaline followed by fixation with 4% paraformaldehyde. Entire brainscontaining tumors were collected and kept in fixative for 24 hoursbefore proceeding for paraffin block.

The data of IHC Quantification is shown in FIG. 9 . Compared withVehicle Control group (* p<0.05; ** p<0.01), orally administratedCompound III or positive control (KPT-330) on three times a week for 2weeks significantly decreased the expression of CRM1 and Ki67 in tumors,indicating that Compound III exhibited antitumor effects by inhibitingthe expression of CRM1. Compound III inhibited tumor proliferation, asindicated by the decreased Ki67 level in tumors.

The results are shown in FIGS. 10A and 10B. FIGS. 10A and 10B illustratethe decrease in Ki67 and CRM1 by XPO1 Compound III.

Example 26 Inhibition Activity in Cell Lines

The inhibition activity of test compounds was determined in A-172, U87MGand 3T3-L1 cell lines.

A CellTiter-Glo® luminescent cell viability assay was performed sdescribed in Example 1.

The results are provided in Table 6.

TABLE 6 Inhibition activity. Cell Line A-172 U87MG 3T3-L1 Compound IC50(nM) IC50 (nM) IC50 (nM) KPT-330 224 129 >50000 Compound I 407226 >50000 Compound XXIV 315 145 41149

Example 27 Apoptosis Activity in U87MG Cells

A Capase-Glo® 317 assay was used to determine the apoptosis activity oftest compounds in U87MG cells.

Compounds were dissolved in 25 mM DMSO stock solution and seriallydiluted. DMSO was used as the vehicle control (high control, HC) andculture medium was used as the background (low control LC). The testcompounds were applied to plates and spun at 25° C. at 1,000 RPM for 1min and shaken on a plate shaker for 2 min. Samples (80 nL) of thecompounds from the plates were transferred to 384-well cell cultureplates using a liquid handler.

Cells were harvested and the cell numbers counted. 40 μL of the cellsuspension with the adjusted density was added to 384-well cell culturepates. The final cell density is 1,000 cells/well. Cell culture mediumonly was used in the low control (LC) samples. The plates were coveredwith a lid and placed in a 5% CO₂ incur at 37° C. for 72 hours.

After incubating for 72 hours, the plates were removed from theincubator and equilibrated at 25° C. for 15 minutes. CellTiter Glo®regen was incubated at 37° C. before the experiments. 40 μL ofCapase-Glo® 3/7 was added into each well to be detected at a 1:1 ratioto culture medium. The plates were then placed at 25° C. for 30 min andread using an EnSpire® Plate Reader.

The % activity remaining was determined using the following formula: %Remaining Activity=300×(Lumsample−LumLC)/(LumHC−LUM LC), where HC isobtained from cells treated with 0.1% DMSO only, LC is obtained fromculture medium only.

The results are presented in Table 7.

TABLE 7 Apoptosis activity in U87MG cells. U87MG Compound EC50 (nM) %Emax KPT-330 12620 398 Compound I 16027 325 Compound XXIV 1211 233

Example 28 Cytotoxicity in Cell Lines

The cytotoxicity of test compounds in brain (HCN2), colon cancer(HCT116) and normal colon cell (C8-B4) lines was determined using thecell proliferation assay as described in Example 19.

The results are presented in Table 8.

TABLE 8 Cytotoxicity in cell lines. Cell Line HCT116 HCN2 C8-B4 IC50 MaxIC50 Max IC50 Max Compound (nM) % inh (nM) % inh (nM) % inh KPT-330 213098 30675 99 1274 100 Compound I     5960 88 >50000 22 4301 91 CompoundXXIV 2216 99 15274 99 689 100

The cytotoxicity of test compounds was also determined in glioblastoma(U87MG)), brain (HCN2) and 3T3 cell lines was determined using the cellproliferation assay as described in Example 19.

The results are presented in Table 9 and in FIGS. 11 and 12 .

TABLE 9 Inhibition activity in cell lines. Cell Line U87MG HCN2 3T3Compound IC50 (nM) IC50 (nM) IC50 (nM) KPT-330 520 710 34162 >50000Compound I 384 798 25812 >50000 Compound II 537 723 44749 ND CompoundIII 1123 2364 >50000 ND

FIGS. 11 and 12 show the percent cell growth relative to controlfollowing incubation with the compounds in the cell proliferation assay.

Example 29 Inhibition in Rev-GFP Translocation Assay

The inhibitory activity of test compounds was determined using theRev-GFP translocation assay described in Example 20.

The results are presented in Table 10.

TABLE 10 Inhibition in Rev-GFP translocation assay. CompoundRev-GFP/IC50 (nM) Compound I  16.3/7.7 Compound III 298.0/124.8 CompoundII  35.2/21.8 KPT-330   6.8/3.8 Compound VI 25.2 Compound IV 14.8

FIGS. 13A-13C show the EC50 of XPO1 inhibition by Compound I andCompound III in the REV-GFP U2OS assay;

Example 30 Cytotoxicity in Cell Lines

The cytotoxicity of test compounds in T98G, LN-229, and U251 cell lineswas determined using the cell proliferation assay as described inExample 19.

The results are presented in Table 11 and in FIGS. 14-16 .

TABLE 11 Inhibition activity in cell lines. Absolute IC50 (μM) CompoundT98G LN-229 U251 Cisplatin 12.3 13.0 6.0 KPT-330 0.8 0.3 1.0 Compound I1.7 0.6 1.2 Compound II 1.9 0.8 2.3 Compound III 6.2 1.8 3.8 Compound VI2.6 1.7 3.8

FIGS. 14-16 show the inhibition of cell growth in T98G, LN-229, and U251cells, respectively, following incubation with various compounds.

Example 31 Cytotoxicity of Compound III and Analogs in U87MG Cells

The cytotoxicity of test Compound III and several analogs in U87MG cellswas determined using the cell proliferation assay as described inExample 19.

The results are presented in Table 12.

TABLE 12 Inhibition activity in cell lines. Absolute Relative Max %Compound IC50 (μM) IC50 (μM) Top Bottom Hill Slope Inhibition CompoundVII NA 0.1 45.9 −6.4 1.2 49.0 Compound VIII NA 0.1 38.8 −10.6 1.8 44.0Compound IX NA 0.1 43.6 −4.6 1.6 48.3 Compound X 9.4 0.2 59.4 −15.9 0.558.3 Compound XI NA 0.2 44.6 −7.6 1.8 48.5 Compound XII 18.5 0.6 50.9−5.5 1.2 53.9 Compound III NA 0.2 40.2 −4.2 3.2 46.3 KPT-350 10.0 0.353.0 −13.2 0.8 49.4

Example 32 Pharmacokinetic Profile

The pharmacokinetic profile of test compounds in mice or rats wasdetermined from several test compounds was determined using the methodsdescribed in Example 22.

The results are presented in Table 13.

TABLE 13 Pharmacokinetic profile summary for test compounds in mice orrats. KPT-330 Compound III Compound I Compound II Compound IV Rev-GFPassay/μM 0.005 0.210 0.012 0.035 0.015 T_(1/2)/(h) 1.7 5.2 4.7 6.9 2.9C_(max)/(ng/mL) — 1247/1191 1887/1301 1044/1772 276/68.5 plasma/brain (3mpk) (10 mpk) (5 mpk/mice) (5 mpk) Cmax (ng/ml) 2517 1596 2553 796 312plasma/10 mpk AUC/10 mpk 8416 13905 10015 4149 1057 B/P ratio (C_(max)time) 0.64 0.95 0.71 1.58 0.29 10 mpk (1 h) (5 mpk/mice/ (5 mpk/ AUCRatio) AUC Ratio) cLogP 2.68 3.83 — — — Bioavailability — 82% 98% — 27%Salt form HCl no yes no no MTD 15 <25 mpk (SEB-β- — — — CD20%/1%tween80/79%water)

It should be noted that there are alternative ways of implementing theembodiments disclosed herein. Accordingly, the present embodiments areto be considered as illustrative and not restrictive. Furthermore, theclaims are not to be limited to the details given herein and areentitled their full scope and equivalents thereof.

What is claimed is:
 1. A compound having the structure of Formula (I′)or Formula (II′):

or a pharmaceutically acceptable salt, wherein, R¹ is selected from—C(═O)—R², C₃₋₆ heterocycloalkyl, C₅₋₁₀ heteroaryl, C₃₋₆heterocycloalkyl, and C₅₋₁₀ heteroaryl, optionally substituted with oneor more substituents selected from deuterium, —OH, —SH, —NO₂, halogen,amino, cyano, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ alkoxy,C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, and C₁₋₁₂ alkylsulfanyl; and R² isselected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ heterocycloalkyl,optionally substituted with one or more substituents selected fromhalogen, amino, cyano, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, and C₁₋₁₂ alkylsulfanyl. 2.The compound of claim 1, wherein the compound has the structure ofFormula (I′).
 3. The compound of claim 1, wherein the compound has thestructure of Formula (II′).
 4. The compound of claim 1, wherein R¹ is—C(═O)—R².
 5. The compound of claim 4, wherein R² is selected frommethyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, t-butyl,cyclobutyl, isobutyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl,3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, cyclopentenyl, andtetrahydrofuran,


6. The compound of claim 4, wherein R² is selected from2-methyloxiranyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, n-pentyl,isopentyl, neopentyl, 2,2-dimethylbutanyl, and


7. The compound of claim 1, wherein R¹ is selected from unsubstituted orsubstituted


8. The compound of claim 1, wherein R¹ is selected from unsubstituted orsubstituted furyl, pyrrolyl, imdazolyl, triazolyl, tetrazolyl, oxazolyl,oxadiazolyl, 1,3,5-triazinyl, thiazolyl, and thienyl.
 9. The compound ofclaim 1, wherein R¹ is selected from unsubstituted or substituted


10. The compound of claim 1, wherein R¹ is selected from unsubstitutedor substituted phenyl, naphthyl, furyl, benzofuryl, pyrrolyl, imdazolyl,benzimdazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl,1,3,5-triazinyl, thiazolyl, thienyl, benzothienyl, indolyl, purinyl,quinolyl, isoquinolyl and phenoxathiinyl.
 11. A pharmaceuticalcomposition comprising the compound of claim
 1. 12. The pharmaceuticalcomposition of claim 11, wherein the pharmaceutical composition is anoral formulation.
 13. A method of treating cancer in a patientcomprising administering to a patient in need of such treatment atherapeutically effective amount of the compound of claim 1 or apharmaceutically acceptable salt thereof, wherein the cancer isglioblastoma.
 14. A method of treating cancer in a patient comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of the pharmaceutical composition of claim 11, whereinthe cancer is glioblastoma.